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1. Leishmania infantum exploits the anti-ferroptosis effects of Nrf2 to escape cell death in macrophages

Author: Clément Blot, Mathilde Lavernhe, Geanncarlo Lugo-Villarino, Kimberley Coulson, Marie Salon, Margot Tertrais, Rémi Planès, Karin Santoni, Hélène Authier, Godefroy Jacquemin, Mouna Rahabi, Mélissa Parny, Isabelle Raymond Letron, Etienne Meunier, Lise Lefèvre, and Agnès Coste
Subjects: CP: Immunology, CP: Microbiology, Biology (General), QH301-705.5
Abstract: Summary: Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis.
Published: 2024
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2. Generation of functionally active resident macrophages from adipose tissue by 3D cultures

Author: Adèle Arlat, Marie-Laure Renoud, Jean Nakhle, Miguel Thomas, Jessica Fontaine, Emmanuelle Arnaud, Cédric Dray, Hélène Authier, Paul Monsarrat, Agnès Coste, Louis Casteilla, Marielle Ousset, and Béatrice Cousin
Subjects: resident macrophage, macrophage subpopulation, adipose tissue, bone marrow, 3D culture, metabolism, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionWithin adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties.MethodsStroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate.ResultsThis innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow–derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages.DiscussionOur study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.
Published: 2024
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3. PPARγ activation modulates the balance of peritoneal macrophage populations to suppress ovarian tumor growth and tumor-induced immunosuppression

Author: Hélène Authier, Agnès Coste, Gwenael Ferron, Mélissa Prat, Augustin Le Naour, Kimberley Coulson, Godefroy Jacquemin, Mouna Chirine Rahabi, Jean-Pierre Delord, Bettina Couderc, Clément Blot, Mathilde Romano, Marie-Laure Renoud, Mohamad AlaEddine, Khaddouj Benmoussa, Marie Salon, Mélissa Parny, and Lise Lefèvre
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target.Methods To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD.Results Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPβ and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites.Conclusion Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.
Published: 2023
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4. Driving regeneration, instead of healing, in adult mammals: the decisive role of resident macrophages through efferocytosis

Author: Lise Rabiller, Virginie Robert, Adèle Arlat, Elodie Labit, Marielle Ousset, Marie Salon, Agnès Coste, Léa Da Costa-Fernandes, Paul Monsarrat, Bruno Ségui, Mireille André, Christophe Guissard, Marie-Laure Renoud, Marine Silva, Gilles Mithieux, Isabelle Raymond-Letron, Luc Pénicaud, Anne Lorsignol, Louis Casteilla, Cécile Dromard Berthézène, and Béatrice Cousin
Subjects: Medicine
Abstract: Abstract Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.
Published: 2021
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5. Variation in chemical composition and antimalarial activities of two samples of Terminalia albida collected from separate sites in Guinea

Author: Aissata Camara, Mohamed Haddad, Mohamed Sahar Traore, Florence Chapeland-Leclerc, Gwenaël Ruprich-Robert, Isabelle Fourasté, Mamadou Aliou Balde, Jade Royo, Melissa Parny, Philippe Batigne, Marie Salon, Agnès Coste, Aliou Mamadou Balde, and Agnès Aubouy
Subjects: Terminalia albida, Malaria, Geographical location, UHPLC-HRMS, Plant molecular analysis, Plasmodium berghei, Other systems of medicine, RZ201-999
Abstract: Abstract Background The disparity of harvesting locations can influence the chemical composition of a plant species, which could affect its quality and bioactivity. Terminalia albida is widely used in traditional Guinean medicine whose activity against malaria has been validated in vitro and in murine models. The present work investigated the antimalarial properties and chemical composition of two samples of T. albida collected from different locations in Guinea. Method T. albida samples were collected in different locations in Guinea, in Dubréka prefecture (West maritime Guinea) and in Kankan prefecture (eastern Guinea). The identity of the samples was confirmed by molecular analysis. In vitro antiplasmodial activity of the two extracts was determined against the chloroquine resistant strain PfK1. In vivo, extracts (100 mg/kg) were tested in two experimental murine models, respectively infected with P. chabaudi chabaudi and P. berghei ANKA. The chemical composition of the two samples was assessed by ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry. Results In vitro, the Dubréka sample (TaD) was more active with an IC50 of 1.5 μg/mL versus 8.5 μg/mL for the extract from Kankan (TaK). In vivo, the antiparasitic effect of TaD was substantial with 56% of parasite inhibition at Day 10 post-infection in P. chabaudi infection and 61% at Day 8 in P. berghei model, compared to 14 and 19% inhibition respectively for the treatment with TaK. In addition, treatment with TaD further improved the survival of P. berghei infected-mice by 50% at Day 20, while the mortality rate of mice treated with Tak was similar to the untreated group. The LC/MS analysis of the two extracts identified 38 compounds, 15 of which were common to both samples while 9 and 14 other compounds were unique to TaD and TaK respectively. Conclusion This study highlights the variability in the chemical composition of the species T. albida when collected in different geographical locations. These chemical disparities were associated with variable antimalarial effects. From a public health perspective, these results underline the importance of defining chemical fingerprints related to botanical species identification and to biological activity, for the plants most commonly used in traditional medicine.
Published: 2021
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6. Synergistic Effects of Licorice Root and Walnut Leaf Extracts on Gastrointestinal Candidiasis, Inflammation and Gut Microbiota Composition in Mice

Author: Hélène Authier, Valérie Bardot, Lucile Berthomier, Bénédicte Bertrand, Claude Blondeau, Sophie Holowacz, and Agnès Coste
Subjects: candidiasis, gut inflammation, licorice, plant extract, prebiotic, walnut, Microbiology, QR1-502
Abstract: ABSTRACT Candida albicans is an opportunistic pathogen that causes gastrointestinal (GI) candidiasis closely associated with intestinal inflammation and dysbiosis. Drug resistance, side effects of available antifungal agents, and the high recurrence of candidiasis highlight the need for new treatments. We investigated the effects of hydroethanolic extracts of licorice root (LRE) and walnut leaf (WLE) on GI colonization by C. albicans, colon inflammation, and gut microbiota composition in C57BL/6 female mice. Oral administration of LRE and WLE alone or in combination once daily for 12 days before C. albicans infection and then for 5 days after infection significantly reduced the level of C. albicans in the feces of gastrointestinal infected mice as well as colonization of the GI tract, both extracts showing robust antifungal activity. Although total bacterial content was unaffected by the extracts (individually or combined), the abundance of protective bacteria, such as Bifidobacterium spp. and Faecalibacterium prausnitzii, increased with the combination, in contrast to that of certain pathobiont bacteria, which decreased. Interestingly, the combination induced a more robust decrease in the expression of proinflammatory genes than either extract alone. The anti-inflammatory activity of the combination was further supported by the reciprocal increase in the expression of anti-inflammatory cytokines and the significant decrease in enzymes involved in the synthesis of proinflammatory eicosanoids and oxidative stress. These findings suggest that LRE and WLE have synergistic effects and that the LRE/WLE combination could be a good candidate for limiting GI candidiasis and associated inflammation, likely by modulating the composition of the gut microbiota. IMPORTANCE The adverse effects and emergence of resistance of currently available antifungals and the high recurrence of candidiasis prompt the need for alternative and complementary strategies. We demonstrated that oral administration of hydroethanolic extracts of licorice root (LRE) and walnut leaf (WLE) separately or in combination significantly reduced the colonization of the gastrointestinal (GI) tract by C. albicans, highlighting a robust antifungal activity of these plant extracts. Interestingly, our data indicate a correlation between LRE and WLE consumption, in particular the combination, and a shift within the gut microbiome toward a protective profile, a decrease in colonic inflammation and prooxidant enzymes, suggesting a synergistic effect. This study highlights the significant prebiotic potential of the LRE/WLE combination and suggests that the health benefits are due, at least in part, to their ability to modulate the gut microbiota, reduce inflammation and oxidative stress, and protect against opportunistic infection.
Published: 2022
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7. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.

Author: Salimata Bagayoko, Stephen Adonai Leon-Icaza, Miriam Pinilla, Audrey Hessel, Karin Santoni, David Péricat, Pierre-Jean Bordignon, Flavie Moreau, Elif Eren, Aurélien Boyancé, Emmanuelle Naser, Lise Lefèvre, Céline Berrone, Nino Iakobachvili, Arnaud Metais, Yoann Rombouts, Geanncarlo Lugo-Villarino, Agnès Coste, Ina Attrée, Dara W Frank, Hans Clevers, Peter J Peters, Céline Cougoule, Rémi Planès, and Etienne Meunier
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.
Published: 2021
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8. Terminalia albida treatment improves survival in experimental cerebral malaria through reactive oxygen species scavenging and anti-inflammatory properties

Author: Aissata Camara, Mohamed Haddad, Karine Reybier, Mohamed Sahar Traoré, Mamadou Aliou Baldé, Jade Royo, Alpha Omar Baldé, Philippe Batigne, Mahamane Haidara, Elhadj Saidou Baldé, Agnès Coste, Aliou Mamadou Baldé, and Agnès Aubouy
Subjects: Terminalia albida, Malaria, Experimental cerebral malaria, Inflammatory response, Oxidative stress, UHPLC-HRMS, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract: Abstract Background The development of Plasmodium resistance to the last effective anti-malarial drugs necessitates the urgent development of new anti-malarial therapeutic strategies. To this end, plants are an important source of new molecules. The objective of this study was to evaluate the anti-malarial effects of Terminalia albida, a plant used in Guinean traditional medicine, as well as its anti-inflammatory and antioxidant properties, which may be useful in treating cases of severe malaria. Methods In vitro antiplasmodial activity was evaluated on a chloroquine-resistant strain of Plasmodium falciparum (K-1). In vivo efficacy of the plant extract was measured in the experimental cerebral malaria model based on Plasmodium berghei (strain ANKA) infection. Mice brains were harvested on Day 7–8 post-infection, and T cells recruitment to the brain, expression levels of pro- and anti-inflammatory markers were measured by flow cytometry, RT-qPCR and ELISA. Non-malarial in vitro models of inflammation and oxidative response were used to confirm Terminalia albida effects. Constituents of Terminalia albida extract were characterized by ultra‐high performance liquid chromatography coupled with high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation patterns. Results In vitro antiplasmodial activity of Terminalia albida was confirmed with an IC50 of 1.5 μg/mL. In vivo, Terminalia albida treatment greatly increased survival rates in P. berghei-infected mice. Treated mice were all alive until Day 12, and the survival rate was 50% on Day 20. Terminalia albida treatment also significantly decreased parasitaemia by 100% on Day 4 and 89% on Day 7 post-infection. In vivo anti-malarial activity was related to anti-inflammatory properties, as Terminalia albida treatment decreased T lymphocyte recruitment and expression of pro-inflammatory markers in brains of treated mice. These properties were confirmed in vitro in the non-malarial model. In vitro, Terminalia albida also demonstrated a remarkable dose-dependent neutralization activity of reactive oxygen species. Twelve compounds were putatively identified in Terminalia albida stem bark. Among them, several molecules already identified may be responsible for the different biological activities observed, especially tannins and triterpenoids. Conclusion The traditional use of Terminalia albida in the treatment of malaria was validated through the combination of in vitro and in vivo studies.
Published: 2019
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9. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

Author: Hélène Authier, Agnès Coste, Alejandra Martinez, Gwenael Ferron, Laurence Gladieff, Mélissa Prat, Augustin Le Naour, Kimberley Coulson, Fanny Lemée, Hélène Leray, Godefroy Jacquemin, Mouna Chirine Rahabi, Léa Lemaitre, Jean-Marc Barret, Maha Ayyoub, Jean-Pierre Delord, Isabelle Tabah-Fisch, Jean-François Prost, and Bettina Couderc
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.Methods In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.Results We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor–associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.Conclusions This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.Trial registration number EudraCT: 2015-004252-22 NCT02978755.
Published: 2020
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10. Oral Administration of Lactobacillus helveticus LA401 and Lactobacillus gasseri LA806 Combination Attenuates Oesophageal and Gastrointestinal Candidiasis and Consequent Gut Inflammation in Mice

Author: Hélène Authier, Marie Salon, Mouna Rahabi, Bénédicte Bertrand, Claude Blondeau, Sarah Kuylle, Sophie Holowacz, and Agnès Coste
Subjects: gastrointestinal candidiasis, gut inflammation, macrophages, Lactobacillus gasseri, Lactobacillus helveticus, probiotic, Biology (General), QH301-705.5
Abstract: Candida albicans is an opportunistic pathogen that causes mucosal gastrointestinal (GI) candidiasis tightly associated with gut inflammatory status. The emergence of drug resistance, the side effects of currently available antifungals and the high frequency of recurrent candidiasis indicate that new and improved therapeutics are needed. Probiotics have been suggested as a useful alternative for the management of candidiasis. We demonstrated that oral administration of Lactobacillus gasseri LA806 alone or combined with Lactobacillus helveticus LA401 in Candida albicans-infected mice decrease the Candida colonization of the oesophageal and GI tract, highlighting a protective role for these strains in C. albicans colonization. Interestingly, the probiotic combination significantly modulates the composition of gut microbiota towards a protective profile and consequently dampens inflammatory and oxidative status in the colon. Moreover, we showed that L. helveticus LA401 and/or L. gasseri LA806 orient macrophages towards a fungicidal phenotype characterized by a C-type lectin receptors signature composed of Dectin-1 and Mannose receptor. Our findings suggest that the use of the LA401 and LA806 combination might be a promising strategy to manage GI candidiasis and the inflammation it causes by inducing the intrinsic antifungal activities of macrophages. Thus, the probiotic combination is a good candidate for managing GI candidiasis by inducing fungicidal functions in macrophages while preserving the GI integrity by modulating the microbiota and inflammation.
Published: 2021
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11. P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARγ Activation

Author: Khaddouj Benmoussa, Hélène Authier, Mélissa Prat, Mohammad AlaEddine, Lise Lefèvre, Mouna Chirine Rahabi, José Bernad, Agnès Aubouy, Elsa Bonnafé, Jérome Leprince, Bernard Pipy, Michel Treilhou, and Agnès Coste
Subjects: Macrophages, host defense peptide, antimicrobial peptides, Candida albicans, C-type lectin receptors, arachidonic acid metabolism, Immunologic diseases. Allergy, RC581-607
Abstract: Despite the growing knowledge with regard to the immunomodulatory properties of host defense peptides, their impact on macrophage differentiation and on its associated microbicidal functions is still poorly understood. Here, we demonstrated that the P17, a new cationic antimicrobial peptide from ant venom, induces an alternative phenotype of human monocyte-derived macrophages (h-MDMs). This phenotype is characterized by a C-type lectin receptors (CLRs) signature composed of mannose receptor (MR) and Dectin-1 expression. Concomitantly, this activation is associated to an inflammatory profile characterized by reactive oxygen species (ROS), interleukin (IL)-1β, and TNF-α release. P17-activated h-MDMs exhibit an improved capacity to recognize and to engulf Candida albicans through the overexpression both of MR and Dectin-1. This upregulation requires arachidonic acid (AA) mobilization and the activation of peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor through the leukotriene B4 (LTB4) production. AA/LTB4/PPARγ/Dectin-1-MR signaling pathway is crucial for P17-mediated anti-fungal activity of h-MDMs, as indicated by the fact that the activation of this axis by P17 triggered ROS production and inflammasome-dependent IL-1β release. Moreover, we showed that the increased anti-fungal immune response of h-MDMs by P17 was dependent on intracellular calcium mobilization triggered by the interaction of P17 with pertussis toxin-sensitive G-protein-coupled receptors on h-MDMs. Finally, we also demonstrated that P17-treated mice infected with C. albicans develop less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf Candida, to produce ROS and IL-1β and to kill the yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts upstream PPARγ/CLRs axis and offer new immunomodulatory therapeutic perspectives in the field of infectious diseases.
Published: 2017
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12. Nrf2, a PPARγ alternative pathway to promote CD36 expression on inflammatory macrophages: implication for malaria.

Author: David Olagnier, Rose-Anne Lavergne, Etienne Meunier, Lise Lefèvre, Christophe Dardenne, Agnès Aubouy, Françoise Benoit-Vical, Bernhard Ryffel, Agnès Coste, Antoine Berry, and Bernard Pipy
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: CD36 is the major receptor mediating nonopsonic phagocytosis of Plasmodium falciparum-parasitized erythrocytes by macrophages. Its expression on macrophages is mainly controlled by the nuclear receptor PPARγ. Here, we demonstrate that inflammatory processes negatively regulate CD36 expression on human and murine macrophages, and hence decrease Plasmodium clearance directly favoring the worsening of malaria infection. This CD36 downregulation in inflammatory conditions is associated with a failure in the expression and activation of PPARγ. Interestingly, using siRNA mediating knock down of Nrf2 in macrophages or Nrf2- and PPARγ-deficient macrophages, we establish that in inflammatory conditions, the Nrf2 transcription factor controls CD36 expression independently of PPARγ. In these conditions, Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and CD36-mediated Plasmodium phagocytosis. These results were confirmed in human macrophages and in vivo where only Nrf2 activators improve the outcome of severe malaria. Collectively, this report highlights that the Nrf2 transcription factor could be an alternative target to PPARγ in the control of severe malaria through parasite clearance.
Published: 2011
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13. PPARγ controls Dectin-1 expression required for host antifungal defense against Candida albicans.

Author: Amandine Galès, Annabelle Conduché, José Bernad, Lise Lefevre, David Olagnier, Maryse Béraud, Guillaume Martin-Blondel, Marie-Denise Linas, Johan Auwerx, Agnès Coste, and Bernard Pipy
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: We recently showed that IL-13 or peroxisome proliferator activated receptor gamma (PPARgamma) ligands attenuate Candida albicans colonization of the gastrointestinal tract. Here, using a macrophage-specific Dectin-1 deficient mice model, we demonstrate that Dectin-1 is essential to control fungal gastrointestinal infection by PPARgamma ligands. We also show that the phagocytosis of yeast and the release of reactive oxygen intermediates in response to Candida albicans challenge are impaired in macrophages from Dectin-1 deficient mice treated with PPARgamma ligands or IL-13. Although the Mannose Receptor is not sufficient to trigger antifungal functions during the alternative activation of macrophages, our data establish the involvement of the Mannose Receptor in the initial recognition of non-opsonized Candida albicans by macrophages. We also demonstrate for the first time that the modulation of Dectin-1 expression by IL-13 involves the PPARgamma signaling pathway. These findings are consistent with a crucial role for PPARgamma in the alternative activation of macrophages by Th2 cytokines. Altogether these data suggest that PPARgamma ligands may be of therapeutic value in esophageal and gastrointestinal candidiasis in patients severely immunocompromised or with metabolic diseases in whom the prevalence of candidiasis is considerable.
Published: 2010
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14. PPARγ ligands switched high fat diet-induced macrophage M2b polarization toward M2a thereby improving intestinal Candida elimination.

Author: Lise Lefèvre, Amandine Galès, David Olagnier, José Bernad, Laurence Perez, Rémy Burcelin, Alexis Valentin, Johan Auwerx, Bernard Pipy, and Agnès Coste
Subjects: Medicine, Science
Abstract: Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. In this metabolic context, gastrointestinal (GI) candidiasis is common. We recently demonstrated that the PPARγ ligand rosiglitazone promotes the clearance of Candida albicans through the activation of alternative M2 macrophage polarization. Here, we evaluated the impact of high fat diet (HFD)-induced obesity and the effect of rosiglitazone (PPARγ ligand) or WY14643 (PPARα ligand) both on the phenotypic M1/M2 polarization of peritoneal and cecal tissue macrophages and on the outcome of GI candidiasis. We demonstrated that the peritoneal macrophages and the cell types present in the cecal tissue from HF fed mice present a M2b polarization (TNF-α(high), IL-10(high), MR, Dectin-1). Interestingly, rosiglitazone induces a phenotypic M2b-to-M2a (TNF-α(low), IL-10(low), MR(high), Dectin-1(high)) switch of peritoneal macrophages and of the cells present in the cecal tissue. The incapacity of WY14643 to switch this polarization toward M2a state, strongly suggests the specific involvement of PPARγ in this mechanism. We showed that in insulin resistant mice, M2b polarization of macrophages present on the site of infection is associated with an increased susceptibility to GI candidiasis, whereas M2a polarization after rosiglitazone treatment favours the GI fungal elimination independently of reduced blood glucose. In conclusion, our data demonstrate a dual benefit of PPARγ ligands because they promote mucosal defence mechanisms against GI candidiasis through M2a macrophage polarization while regulating blood glucose level.
Published: 2010
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15. Data from IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells

Author: Agnès Coste, Bernard Pipy, Bettina Couderc, François Couderc, Patricia Balard, Bruno Segui, Laurent Alric, José Bernad, Christophe Dardenne, Camille Alric, Lise Lefèvre, Etienne Meunier, Hélène Authier, Valérie Gouazé-Andersson, Véréna Poinsot, Mélissa Prat, and Mohamad Alaeddine
Abstract: Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell lymphoma and ovarian adenocarcinoma development in tumor-bearing mice through the conversion of tumor-supporting macrophages to cytotoxic effectors, characterized by a CLR signature composed of dectin-1 and mannose receptor (MR). We show that dectin-1 and MR are critical for the recognition of tumor cells through sialic acid–specific glycan structure on their surface and for the subsequent activation of macrophage tumoricidal response. Finally, we validated that IL13 antitumor effect mediated by dectin-1 and MR overexpression on macrophages can extend to various types of human tumors. Therefore, these results identify these CLRs as potential targets to promote macrophage antitumor response and represent an attractive approach to elicit tumor-associated macrophage tumoricidal properties.
Published: 2023
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16. Supplementary table 1 from IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells

Author: Agnès Coste, Bernard Pipy, Bettina Couderc, François Couderc, Patricia Balard, Bruno Segui, Laurent Alric, José Bernad, Christophe Dardenne, Camille Alric, Lise Lefèvre, Etienne Meunier, Hélène Authier, Valérie Gouazé-Andersson, Véréna Poinsot, Mélissa Prat, and Mohamad Alaeddine
Abstract: Primer sequences
Published: 2023
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17. Supplementary Figures from IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells

Author: Agnès Coste, Bernard Pipy, Bettina Couderc, François Couderc, Patricia Balard, Bruno Segui, Laurent Alric, José Bernad, Christophe Dardenne, Camille Alric, Lise Lefèvre, Etienne Meunier, Hélène Authier, Valérie Gouazé-Andersson, Véréna Poinsot, Mélissa Prat, and Mohamad Alaeddine
Abstract: Figure S1-Figure S8
Published: 2023
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18. The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors

Author: Marie Rouanet, Naima Hanoun, null Hubert Lulka, Cindy Ferreira, Pierre Garcin, Martin Sramek, Godefroy Jacquemin, Agnès Coste, Delphine Pagan, Carine Valle, Emeline Sarot, Vera Pancaldi, Frédéric Lopez, Louis Buscail, and Pierre Cordelier
Subjects: Pharmacology, Membrane Glycoproteins, Macrophages, Ligands, Pancreatic Neoplasms, Mice, Toll-Like Receptor 7, Drug Discovery, Tumor Microenvironment, Genetics, Animals, Humans, Molecular Medicine, Original Article, Molecular Biology
Abstract: Toll-like receptors (TLRs) are key players in the innate immune system. Recent studies have suggested that they may affect the growth of pancreatic cancer, a disease with no cure. Among them, TLR7 shows promise for therapy but may also promotes tumor growth. Thus, we aimed to clarify the therapeutic potential of TLR7 ligands in experimental pancreatic cancer models, to open the door for clinical applications. In vitro, we found that TLR7 ligands strongly inhibit the proliferation of both human and murine pancreatic cancer cells, compared with TLR2 agonists. Hence, TLR7 treatment alters cancer cells' cell cycle and induces cell death by apoptosis. In vivo, TLR7 agonist therapy significantly delays the growth of murine pancreatic tumors engrafted in immunodeficient mice. Remarkably, TLR7 ligands administration instead increases tumor growth and accelerates animal death when tumors are engrafted in immunocompetent models. Further investigations revealed that TLR7 agonists modulate the intratumoral content and phenotype of macrophages and that depleting such tumor-associated macrophages strongly hampers TLR7 agonist-induced tumor growth. Collectively, our findings shine a light on the duality of action of TLR7 agonists in experimental cancer models and call into question their use for pancreatic cancer therapy.
Published: 2022
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19. Bioactive fish collagen peptides weaken intestinal inflammation by orienting colonic macrophages phenotype through mannose receptor activation

Author: Mouna Rahabi, Marie Salon, Christelle Bruno-Bonnet, Mélissa Prat, Godefroy Jacquemin, Khaddouj Benmoussa, Mohamad Alaeddine, Mélissa Parny, José Bernad, Bénédicte Bertrand, Yannick Auffret, Pascale Robert-Jolimaître, Laurent Alric, Hélène Authier, and Agnès Coste
Subjects: Inflammation, Nutrition and Dietetics, Colon, Macrophages, Dextran Sulfate, Anti-Inflammatory Agents, Medicine (miscellaneous), Colitis, Inflammatory Bowel Diseases, Antioxidants, Mice, Inbred C57BL, Disease Models, Animal, Mice, Phenotype, Animals, Humans, Collagen, Peptides, Mannose, Mannose Receptor
Abstract: Purpose Particular interest is now given to the potential of dietary supplements as alternative non-pharmacological approaches in intestinal inflammation handling. In this aim, this study evaluates the efficiency of fish collagen peptides, Naticol®Gut, on colonic inflammation. Methods Wild type and Mannose receptor-deficient in the myeloid lineage C57BL/6 mice were administered with Dextran Sodium Sulfate (DSS), Naticol®Gut, DSS, and Naticol®Gut or only water for 4 or 8 days. Inflammatory status was evaluated by establishing macroscopic and microscopic scores, by measuring cytokine and calprotectin production by ELISA and the myeloperoxidase activity by chemiluminescence. Colonic macrophages were phenotyped by measuring mRNA levels of specific markers of inflammation and oxidative status. Colonic immune populations and T-cell activation profiles were determined by flow cytometry. Mucosa-associated gut microbiota assessment was undertaken by qPCR. The phenotype of human blood monocytes from inflammatory bowel disease (IBD) subjects was characterized by RT-qPCR and flow cytometry and their oxidative activity by chemiluminescence. Results Naticol®Gut-treated DSS mice showed attenuated colonic inflammation compared to mice that were only exposed to DSS. Naticol®Gut activity was displayed through its ability to orient the polarization of colonic macrophage towards an anti-inflammatory and anti-oxidant phenotype after its recognition by the mannose receptor. Subsequently, Naticol®Gut delivery modulated CD4 T cells in favor of a Th2 response and dampened CD8 T-cell activation. This immunomodulation resulted in an intestinal eubiosis. In human monocytes from IBD subjects, the treatment with Naticol®Gut also restored an anti-inflammatory and anti-oxidant phenotype. Conclusion Naticol®Gut acts as a protective agent against colitis appearing as a new functional food and an innovative and complementary approach in gut health.
Published: 2022
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20. Driving regeneration, instead of healing, in adult mammals: the decisive role of resident macrophages through efferocytosis

Author: Anne Lorsignol, Isabelle Raymond-Letron, Léa Da Costa-Fernandes, Lise Rabiller, Béatrice Cousin, Marine Silva, Adèle Arlat, Elodie Labit, Paul Monsarrat, Agnès Coste, Bruno Ségui, Gilles Mithieux, Marie-Laure Renoud, Mireille André, Cécile Dromard Berthézène, Marie Salon, Luc Pénicaud, Virginie Robert, Marielle Ousset, Christophe Guissard, Louis Casteilla, STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Calgary, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, diabète et cerveau, Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cell biology, Physiology, [SDV]Life Sciences [q-bio], Immunology, Biomedical Engineering, Medicine (miscellaneous), Granulocyte, Biology, Regenerative medicine, Article, Lesion, 03 medical and health sciences, 0302 clinical medicine, medicine, Efferocytosis, Tissue homeostasis, Loss function, 030304 developmental biology, 0303 health sciences, Regeneration (biology), 3. Good health, Haematopoiesis, medicine.anatomical_structure, Medicine, medicine.symptom, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.
Published: 2021
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21. Differential immunomodulatory effects of six pesticides of different chemical classes on human monocyte-derived macrophage functions

Author: Melissa Parny, Agnès Coste, Agnès Aubouy, Mouna Rahabi, Melissa Prat, Bernard Pipy, and Michel Treilhou
Subjects: Macrophages, Cytokines, Humans, General Medicine, Chlorpyrifos, RNA, Messenger, Pesticides, Toxicology, Reactive Oxygen Species, Thiophanate, Food Science, Captan
Abstract: Exposure to pesticides through eyes, skin, ingestion and inhalation may affects human health by interfering with immune cells, such as macrophages. We evaluated, in vitro, the effect of six pesticides widely used in apple arboriculture on the functions of human monocyte-derived macrophages (hMDMs). hMDMs were cultured for 4 or 24 h with or without pesticides (0.01, 0.1, 1, 10 μmol.L
Published: 2021

22. Murlentamab, a Low Fucosylated Anti-Müllerian Hormone Type II Receptor (AMHRII) Antibody, Exhibits Anti-Tumor Activity through Tumor-Associated Macrophage Reprogrammation and T Cell Activation

Author: Mélissa Prat, Marie Salon, Thibault Allain, Olivier Dubreuil, Grégory Noël, Laurence Preisser, Bérangère Jean, Lydie Cassard, Fanny Lemée, Isabelle Tabah-Fish, Bernard Pipy, Pascale Jeannin, Jean-François Prost, Jean-Marc Barret, Agnès Coste, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GamaMabs Pharma SA [Toulouse] ( Centre Pierre Potier), Oncopole de Toulouse-Centre Pierre Potier [Toulouse], Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Gustave Roussy (IGR), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bernardo, Elizabeth, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: glyco-engineered antibody, ovarian cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, tumor-associated macrophages, murlentamab, [SDV.CAN]Life Sciences [q-bio]/Cancer, adaptive immunity, immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article
Abstract: Simple Summary AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs in healthy adults but is also re-expressed in ovarian, colorectal and lung cancers. In this context, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody, currently in clinical trial. Preliminary data suggest that murlentamab anti-tumor activity involves immune response activation. Thus, in vitro experiments were performed to precisely characterize the murlentamab effect on the human immune system. We show that murlentamab treatment is associated with evidences of innate and adaptive immune cell activation in cancer patient samples. Moreover, we demonstrate that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells promotes a polarization switch of both naïve and tumor-associated macrophages towards an anti-tumor M1-like phenotype. Our work also supports that, through macrophage reeducation, murlentamab activates an anti-tumor adaptive immune response. Finally, the combination of murlentamab with pembrolizumab confirmed novel clinical perspectives of murlentamab association with checkpoint inhibitors and other immuno-modulators. Abstract AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4+ Th1/Th2 balance towards a Th1 response and activates CD8+ T cells. Altogether, these results suggest that murlentamab, through naïve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced cancer patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives.
Published: 2021
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23. Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Author: Aurélien Boyance, Karin Santoni, Stephen Adonai Leon-Icaza, Hans Clevers, Yoann Rombouts, Arnaud Métais, Etienne Meunier, Agnès Coste, Emmanuelle Naser, Ina Attrée, Peter J. Peters, Rémi Planès, Audrey Hessel, Elif Eren, Salimata Bagayoko, Céline Berrone, Céline Cougoule, N. Iacobachvili, Pierre-Jean Bordignon, Miriam Pinilla, Flavie Moreau, Lise Lefèvre, and Dara W. Frank
Subjects: Pathology, medicine.medical_specialty, Necrosis, Chemistry, Pseudomonas aeruginosa, Phospholipid, Virulence, Phospholipase, GPX4, medicine.disease_cause, Lipid peroxidation, chemistry.chemical_compound, Immune system, medicine, medicine.symptom
Abstract: SummaryRegulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage.Pseudomonas aeruginosaexpresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial eliminationin vitroandin vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogenBurkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.
Published: 2021
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24. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports $Pseudomonas\ aeruginosa$-driven pathology

Author: Flavie Moreau, Geanncarlo Lugo-Villarino, Aurélien Boyance, Arnaud Métais, Peter J. Peters, Karin Santoni, Céline Cougoule, Stephen Adonai Leon-Icaza, Hans Clevers, Lise Lefèvre, Etienne Meunier, Yoann Rombouts, Agnès Coste, Pierre-Jean Bordignon, Miriam Pinilla, Emmanuelle Naser, Audrey Hessel, David Péricat, Ina Attrée, Rémi Planès, Nino Iakobachvili, Dara W. Frank, Elif Eren, Salimata Bagayoko, Céline Berrone, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maastricht University [Maastricht], Groupe Pathogenèse Bactérienne et Réponses Cellulaires / Bacterial Pathogenesis and Cellular Responses Group (IBS-PBRC), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Medical College of Wisconsin [Milwaukee] (MCW), Hubrecht Institute [Utrecht, Netherlands], University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW), ANR-18-CE14-0007,ENDIABAC,LE SYSTEME NERVEUX ENTERIQUE COMME CIBLE POUR TRAITER LE DIABETE DE TYPE 2 : ROLES DES LIPIDES BIOACTIFS BACTERIENS(2018), ANR-17-CE11-0006,MacGlycoTB,Rôle de ST8SIA4 et de la polysialylation des protéines des macrophages dans la réponse immunitaire contre une infection par Mycobacterium tuberculosis(2017), European Project: 804249,INFLAME, Hubrecht Institute for Developmental Biology and Stem Cell Research, ATTREE, Ina, APPEL À PROJETS GÉNÉRIQUE 2018 - LE SYSTEME NERVEUX ENTERIQUE COMME CIBLE POUR TRAITER LE DIABETE DE TYPE 2 : ROLES DES LIPIDES BIOACTIFS BACTERIENS - - ENDIABAC2018 - ANR-18-CE14-0007 - AAPG2018 - VALID, Rôle de ST8SIA4 et de la polysialylation des protéines des macrophages dans la réponse immunitaire contre une infection par Mycobacterium tuberculosis - - MacGlycoTB2017 - ANR-17-CE11-0006 - AAPG2017 - VALID, Deciphering the host and microbial grounds that license inflammasome-mediated execution - INFLAME - 804249 - INCOMING, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, RS: M4I - Nanoscopy, and Institute of Nanoscopy (IoN)
Subjects: Pathology, Hydrolases, Necrosis/metabolism, GPX4, Pathology and Laboratory Medicine, Biochemistry, Lipid peroxidation, Mice, 0302 clinical medicine, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), 0303 health sciences, Bacterial Proteins/metabolism, Esterases, Lipids, 3. Good health, Bacterial Pathogens, Pseudomonas aeruginosa/metabolism, Organoids, Medical Microbiology, Biological Cultures, Cellular Types, medicine.medical_specialty, QH301-705.5, Virulence/physiology, Knockout, Immune Cells, Immunology, Virulence, PATATIN-LIKE PHOSPHOLIPASES, Transfection, Microbiology, 03 medical and health sciences, IMMUNE RECOGNITION, Necrosis, Signs and Symptoms, Bacterial Proteins, Pseudomonas, Genetics, A(2) ENZYMES, Humans, Pseudomonas Infections, CYTOTOXIN EXOU, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Lipid Peroxidation/physiology, Blood Cells, Bacteria, Macrophages, Organisms, Biology and Life Sciences, Proteins, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitology, Lipid Peroxidation, Immunologic diseases. Allergy, Clinical Medicine, 030217 neurology & neurosurgery, Phospholipase, medicine.disease_cause, chemistry.chemical_compound, White Blood Cells, Medicine and Health Sciences, OXIDATIVE STRESS, Organ Cultures, Phospholipids, Mice, Knockout, Chemistry, DEATH, Pseudomonas Aeruginosa, LIPID-PEROXIDATION, Enzymes, Host-Pathogen Interactions/physiology, Phospholipases, SECRETION SYSTEM, Host-Pathogen Interactions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine.symptom, Pathogens, Research Article, Phospholipid, Research and Analysis Methods, Immune system, Virology, medicine, Animals, 030304 developmental biology, Pseudomonas aeruginosa, Pseudomonas Infections/metabolism, Cell Biology, RC581-607, FERROPTOSIS, Enzymology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology., Author summary Although a proper activation of various regulated cell necrosis confer a significant advantage against various infectious agents, their dysregulation drives host tissue damages that can end up with fatal sepsis. Specifically, 30% of the bacterial strains of Pseudomonas aeruginosa (P. aeruginosa) express the phospholipase A2-like toxin ExoU that is injected into host target cells through the Type-3 Secretion System. This toxin induces, through a yet unknown mechanism, a strong and fast necrotic cell death that supports fatal respiratory infections. Therefore, in this study, we sought to determine the cellular mechanisms by which ExoU triggers host cell necrosis. In this context, we found that ExoU exploits basal cellular phospholipid peroxidation to promote cell necrosis. Mechanistically, host cell lipid peroxidation stimulates ExoU phospholipase activity, which then triggers a pathological cell necrosis both in vitro and in vivo. Altogether, our results unveil that targeting host cell lipid peroxidation constitutes a virulence mechanism developed by microbial phospholipases, a process that contributes to P. aeruginosa-mediated pathology.
Published: 2021
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25. Variation in chemical composition and antimalarial activities of two samples of Terminalia albida collected from separate sites in Guinea

Author: Mohamed Sahar Traore, Aïssata Camara, Gwenaël Ruprich-Robert, Mohamed Haddad, Isabelle Fourasté, Marie Salon, Melissa Parny, Philippe Batigne, Jade Royo, Agnès Aubouy, Mamadou Aliou Baldé, Florence Chapeland-Leclerc, Aliou Mamadou Balde, and Agnès Coste
Subjects: Male, Plasmodium, Antiparasitic, medicine.drug_class, Plasmodium berghei, 030231 tropical medicine, Plant molecular analysis, 01 natural sciences, Plasmodium chabaudi, 03 medical and health sciences, Antimalarials, 0302 clinical medicine, Species Specificity, In vivo, Chloroquine, Terminalia albida, parasitic diseases, medicine, UHPLC-HRMS, Parasite hosting, Animals, Geographical location, Chemical composition, Medicine, African Traditional, biology, Traditional medicine, Plant Extracts, Biological activity, lcsh:Other systems of medicine, lcsh:RZ201-999, biology.organism_classification, 0104 chemical sciences, Malaria, Mice, Inbred C57BL, 010404 medicinal & biomolecular chemistry, Complementary and alternative medicine, Terminalia, Female, Guinea, Human medicine, medicine.drug, Phytotherapy, Research Article
Abstract: Background The disparity of harvesting locations can influence the chemical composition of a plant species, which could affect its quality and bioactivity. Terminalia albida is widely used in traditional Guinean medicine whose activity against malaria has been validated in vitro and in murine models. The present work investigated the antimalarial properties and chemical composition of two samples of T. albida collected from different locations in Guinea. Method T. albida samples were collected in different locations in Guinea, in Dubréka prefecture (West maritime Guinea) and in Kankan prefecture (eastern Guinea). The identity of the samples was confirmed by molecular analysis. In vitro antiplasmodial activity of the two extracts was determined against the chloroquine resistant strain PfK1. In vivo, extracts (100 mg/kg) were tested in two experimental murine models, respectively infected with P. chabaudi chabaudi and P. berghei ANKA. The chemical composition of the two samples was assessed by ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry. Results In vitro, the Dubréka sample (TaD) was more active with an IC50 of 1.5 μg/mL versus 8.5 μg/mL for the extract from Kankan (TaK). In vivo, the antiparasitic effect of TaD was substantial with 56% of parasite inhibition at Day 10 post-infection in P. chabaudi infection and 61% at Day 8 in P. berghei model, compared to 14 and 19% inhibition respectively for the treatment with TaK. In addition, treatment with TaD further improved the survival of P. berghei infected-mice by 50% at Day 20, while the mortality rate of mice treated with Tak was similar to the untreated group. The LC/MS analysis of the two extracts identified 38 compounds, 15 of which were common to both samples while 9 and 14 other compounds were unique to TaD and TaK respectively. Conclusion This study highlights the variability in the chemical composition of the species T. albida when collected in different geographical locations. These chemical disparities were associated with variable antimalarial effects. From a public health perspective, these results underline the importance of defining chemical fingerprints related to botanical species identification and to biological activity, for the plants most commonly used in traditional medicine.
Published: 2021

26. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

Author: Godefroy Jacquemin, Bettina Couderc, Augustin Le Naour, Gwenael Ferron, Kimberley Coulson, Jean-Marc Barret, Hélène Leray, Hélène Authier, Maha Ayyoub, Jean-Pierre Delord, Lea Lemaitre, Isabelle Tabah-Fisch, Jean-François Prost, Mouna Rahabi, Alejandra Martinez, Agnès Coste, Mélissa Prat, Fanny Lemée, and Laurence Gladieff
Subjects: Oncology, Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Immunology, Short Report, Lipopolysaccharide Receptors, Monocytes, Immune system, biomarkers, tumor, Internal medicine, Ascites, medicine, Tumor Microenvironment, Immunology and Allergy, Humans, RC254-282, Pharmacology, Tumor microenvironment, business.industry, Receptors, IgG, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosuppression, Immunotherapy, medicine.disease, immunity, macrophages, Tumor progression, Disease Progression, Molecular Medicine, Biomarker (medicine), Female, medicine.symptom, business, Ovarian cancer
Abstract: BackgroundBesides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.MethodsIn this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.ResultsWe demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor–associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.ConclusionsThis study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.Trial registration numberEudraCT: 2015-004252-22NCT02978755.
Published: 2020

27. Divergent Roles for Macrophage C-type Lectin Receptors, Dectin-1 and Mannose Receptors, in the Intestinal Inflammatory Response

Author: Mouna Rahabi, Godefroy Jacquemin, Mélissa Prat, Etienne Meunier, Mohamad AlaEddine, Bénédicte Bertrand, Lise Lefèvre, Khaddouj Benmoussa, Philippe Batigne, Agnès Aubouy, Johan Auwerx, Sylvain Kirzin, Delphine Bonnet, Marie Danjoux, Bernard Pipy, Laurent Alric, Hélène Authier, Agnès Coste
Published: 2020
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28. Comparative study of the effects of ziram and disulfiram on human monocyte-derived macrophage functions and polarization : involvement of zinc

Author: Bernard Pipy, Agnès Aubouy, Elsa Bonnafé, Marie Salon, Agnès Coste, Mélissa Prat, José Bernad, Michel Treilhou, and Melissa Parny
Subjects: 0301 basic medicine, Health, Toxicology and Mutagenesis, Interleukin-1beta, Macrophage polarization, SOD2, Apoptosis, Pharmacology, Toxicology, medicine.disease_cause, Antioxidants, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phagocytosis, Ziram, Polarization, Disulfiram, medicine, Humans, Pesticides, Chemokine CCL2, Interleukin-6, Tumor Necrosis Factor-alpha, Chemistry, Macrophages, Zymosan, Cell Polarity, Cell Biology, Oxidative burst, Fungicides, Industrial, Respiratory burst, Oxidative Stress, Zinc, 030104 developmental biology, 030220 oncology & carcinogenesis, Cytokines, CD163, Oxidative stress, medicine.drug
Abstract: Ziram, a zinc dithiocarbamate is widely used worldwide as a fungicide in agriculture. In order to investigate ziram-induced changes in macrophage functions and polarization, human monocytes-derived macrophages in culture were treated with ziram at 0.01-10 mu mol.L(-1)for 4-24 h. To characterize zinc involvement in these changes, we also determined the effects of disulfiram alone (dithiocarbamate without zinc) or in co-incubation with ZnSO4. We have shown that ziram and disulfiram at 0.01 mu mol.L(-1)increased zymosan phagocytosis. In contrast, ziram at 10 mu mol.L(-1)completely inhibited this phagocytic process, the oxidative burst triggered by zymosan and the production of TNF-alpha, IL-1 beta, IL-6, and CCL2 triggered by LPS. Disulfiram had the same effects on these macrophages functions only when combined with zinc (10 mu mol.L-1). In contrast, at 10 mu mol.L(-1)ziram and zinc associated-disulfiram induced expression of several antioxidants genes HMOX1, SOD2, and catalase, which could suggest the induction of oxidative stress. This oxidative stress could be involved in the increase in late apoptosis induced by ziram (10 mu mol.L-1) and zinc associated-disulfiram. Concerning gene expression profiles of membrane markers of macrophage polarization, ziram at 10 mu mol.L(-1)had two opposite effects. It inhibited the gene expression of M2 markers (CD36, CD163) in the same way as the disulfiram-zinc co-treatment. Conversely, ziram induced gene expression of other M2 markers CD209, CD11b, and CD16 in the same way as treatment with zinc alone. Disulfiram-zinc association had no significant effects on these markers. These results taken together show that ziram via zinc modulates macrophages to M2-like anti-inflammatory phenotype which is often associated with various diseases.
Published: 2020

29. Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors

Author: Alejandra Martinez, Renaud Mével, Jean-Pierre Delord, Lise Lefèvre, Muriel Golzio, Eliane Mery, Marie-Véronique Joubert, Kimberley Coulson, Agnès Coste, Gwenael Ferron, Mélissa Prat, Hélène Leray, Benoît Thibault, Léa Lemaitre, Bettina Couderc, Augustin Le Naour, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut Claudius Regaud. Department of pathology, Group of Intelligent and Cooperative Systems / Education,Media, Informatics and Culture (GSIC/EMIC), Universidad de Valladolid [Valladolid] (UVa), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté des Sciences Pharmaceutiques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: ovarian adenocarcinoma, Chemokine, Biopsy, chemokines, Cell Communication, Mice, Ovarian tumor, 0302 clinical medicine, Neoplasms, Tumor Microenvironment, CXC chemokine receptors, ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, 0303 health sciences, biology, Chemistry, chemoresistance, Cell Differentiation, General Medicine, 3. Good health, CXCL2, 030220 oncology & carcinogenesis, Cytokines, Female, mesenchymal stromal cells, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Models, Biological, Article, Immunomodulation, 03 medical and health sciences, Cell Line, Tumor, Genetics, Animals, Humans, Immunologic Factors, Interleukin 8, Molecular Biology, 030304 developmental biology, Receptors, CXCR, Gene Expression Profiling, Macrophages, Mesenchymal stem cell, Computational Biology, Mesenchymal Stem Cells, Cell Biology, Editor's Choice, Disease Models, Animal, Drug Resistance, Neoplasm, Tumor progression, Cancer cell, biology.protein, Cancer research, Biomarkers
Abstract: Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients’ blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.
Published: 2019
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30. Type-3 Secretion System–induced pyroptosis protects Pseudomonas against cell-autonomous immunity

Author: Roland F. Dreier, Julien M. Buyck, Olivier Cunrath, Petr Broz, Rémi Planès, Dirk Bumann, Emmanuelle Naser, Elif Eren, José Carlos Santos, Valérie Duplan-Eche, Agnès Coste, Olivier Neyrolles, Etienne Meunier, Pierre-Jean Bordignon, Céline Cougoule, André Colom, and Antonio Peixoto
Subjects: Innate immune system, Pseudomonas aeruginosa, Intracellular parasite, Pyroptosis, Inflammasome, biochemical phenomena, metabolism, and nutrition, Biology, medicine.disease_cause, Microbiology, Immune system, medicine, bacteria, Macrophage, Efferocytosis, medicine.drug
Abstract: Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process against intracellular bacteria, namely the generation of dying cell structures. These so-called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. However, the immune importance of pyroptosis against extracellular pathogens remains unclear. Here, we report that Type-3 secretion system (T3SS)-expressingPseudomonas aeruginosa(P. aeruginosa) escaped PIT immunity by inducing a NLRC4 inflammasome-dependent macrophage pyroptosis response in the extracellular environment. To the contrary, phagocytosis ofSalmonellaTyphimurium promoted NLRC4-dependent PIT formation and the subsequent bacterial caging. Remarkably, T3SS-deficientPseudomonaswere efficiently sequestered within PIT-dependent caging, which favored exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice presented increased susceptibility to T3SS-deficientP. aeruginosachallenge, but not to T3SS-expressingP. aeruginosa.Overall, our results uncovered thatP. aeruginosauses its T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against intracellular invaders.ImportanceAlthough innate immune components confer host protection against infections, the opportunistic bacterial pathogenPseudomonas aeruginosa(P. aeruginosa) exploits the inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune complex, triggers an Interleukin (IL)-1β and -18 deleterious host response toP. aeruginosa. Here, we provide evidence that, in addition to IL-1 cytokines,P. aeruginosaalso exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study reveals that pyroptosis-driven immune effectiveness mainly depends onP. aeruginosalocalization. This paves the way toward our comprehension of the mechanistic requirements for pyroptosis effectiveness upon microbial infections and may initiate targeted approaches in order to ameliorate the innate immune functions to infections.Graphical abstractMacrophages infected with T3SS-expressingP. aeruginosadie in a NLRC4-dependent manner, which allows bacterial escape from PIT-mediated cell-autonomous immunity and neutrophil efferocytosis. However, T3SS-deficientP. aeruginosais detected by both NLRC4 and caspase-11 inflammasomes, which promotes bacterial trapping and subsequent efferocytosis ofP. aeruginosa-containing-PITs by neutrophils.
Published: 2019
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31. IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells

Author: François Couderc, Camille Alric, Christophe Dardenne, Bettina Couderc, Bruno Ségui, José Bernad, Lise Lefèvre, Mélissa Prat, Bernard Pipy, Etienne Meunier, Agnès Coste, Patricia Balard, Laurent Alric, Hélène Authier, Véréna Poinsot, Mohamad Alaeddine, Valérie Gouazé-Andersson, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Nutergia, This research was supported by a grant from CIFRE-Association Nationale de la Recherche et de la Technologie (ANRT) awarded to M. Alaeddine (2012/1416) and from the Nutergia Laboratory (to A. Coste and B. Pipy), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BIBAC - Chimie analytique et interactions biomolécules - matière molle biomimétique (BIBAC), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR50, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Astrophysique de Marseille (LAM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Centre National d'Études Spatiales [Toulouse] (CNES), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Necrosis / immunology, Mice Knockout, T-Lymphocytes, Receptor expression, Gene Expression, Macrophages / immunology, Mice, 0302 clinical medicine, Interleukin-13 / genetics, N-Acetylneuraminic Acid / metabolism, Neoplasms, Arginase / metabolism, Lectins, Mannose-Binding Lectins / genetics, Receptors, Macrophage, Cytotoxic T cell, Neoplasms / etiology, Receptor, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, Neoplasms / metabolism, Mice, Knockout, Interleukin-13, Tumor, Chemistry, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Signal transduction, Mannose Receptor, Mannose receptor, C-Type / metabolism, Signal Transduction, Immunology, Interleukin-13 / metabolism, Receptors, Cell Surface, Cell Line, Necrosis, 03 medical and health sciences, Cell Surface / genetics, C-Type / genetics, Cell Line, Tumor, Macrophages / metabolism, Animals, Humans, [CHIM]Chemical Sciences, Lectins, C-Type, Mannose-Binding Lectins / metabolism, Cell Surface / metabolism, Neoplasms / pathology, Arginase, Macrophages, T-Lymphocytes / immunology, Reactive Oxygen Species / metabolism, N-Acetylneuraminic Acid, Neoplasms / mortality, Mannose-Binding Lectins, Cell culture, Cancer research, Necrosis / genetics, Reactive Oxygen Species, T-Lymphocytes / metabolism, 030215 immunology
Abstract: Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell lymphoma and ovarian adenocarcinoma development in tumor-bearing mice through the conversion of tumor-supporting macrophages to cytotoxic effectors, characterized by a CLR signature composed of dectin-1 and mannose receptor (MR). We show that dectin-1 and MR are critical for the recognition of tumor cells through sialic acid–specific glycan structure on their surface and for the subsequent activation of macrophage tumoricidal response. Finally, we validated that IL13 antitumor effect mediated by dectin-1 and MR overexpression on macrophages can extend to various types of human tumors. Therefore, these results identify these CLRs as potential targets to promote macrophage antitumor response and represent an attractive approach to elicit tumor-associated macrophage tumoricidal properties.
Published: 2019
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32. Divergent Roles for Macrophage C-Type Lectin Receptors, Dectin-1 and Mannose Receptors, in Inflammatory Bowel Diseases

Author: Bernard Pipy, Mohamad Alaeddine, Delphine Bonnet, Sylvain Kirzin, Hélène Authier, Godefroy Jacquemin, Mouna Rahabi, Marie Danjoux, Johan Auwerx, Lise Lefèvre, Agnès Aubouy, Khaddouj Benmoussa, Agnès Coste, Etienne Meunier, Bénédicte Bertrand, Laurent Alric, Philippe Batigne, and Mélissa Prat
Subjects: education.field_of_study, Innate immune system, Leukotriene B4, business.industry, Monocyte, Population, Inflammation, medicine.disease, digestive system diseases, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Immunology, medicine, Macrophage, Colitis, medicine.symptom, education, business, Mannose receptor
Abstract: Colonic macrophages are considered as major effectors of inflammatory bowel diseases (IBD), and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis the loss of Dectin-1 prevents intestinal inflammation, while the lack of MR exacerbates it. A marked increase in Dectin-1 expression in DSS-exposed MR-deficient mice, support the critical contribution of Dectin-1 in the development of colitis. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of M1 inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent IL-1β secretion through the leukotriene B4 production. Interestingly, the colonic inflammation is associated with a concomitant overexpression of Dectin-1/CCL2/LTA4H and a down-regulation of MR on macrophages from IBD patients. Thus, MR and Dectin-1 on macrophage are important mucosal inflammatory regulators during IBD. Finally, this study offers breakthroughs on the mechanism may contribute to the pathogenesis of IBD in humans.
Published: 2019
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33. Oral Administration of Lactobacillus helveticus LA401 and Lactobacillus gasseri LA806 Combination Attenuates Oesophageal and Gastrointestinal Candidiasis and Consequent Gut Inflammation in Mice

Author: Sophie Holowacz, Bénédicte Bertrand, Agnès Coste, Hélène Authier, Sarah Kuylle, Marie Salon, Mouna Rahabi, Claude Blondeau, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), PiLeJe Laboratoire, and Genibio [Lorp-Sentaraille]
Subjects: Microbiology (medical), C-type lectin receptor, [SDV]Life Sciences [q-bio], Inflammation, Plant Science, Gut flora, Lactobacillus gasseri, Lactobacillus helveticus, Article, Microbiology, law.invention, 03 medical and health sciences, Probiotic, 0302 clinical medicine, law, medicine, Candida albicans, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, mannose receptor, 030304 developmental biology, 0303 health sciences, biology, business.industry, biology.organism_classification, Corpus albicans, macrophages, lcsh:Biology (General), 030220 oncology & carcinogenesis, gut inflammation, dectin-1, medicine.symptom, business, gastrointestinal candidiasis, probiotic, Mannose receptor
Abstract: Candida albicans is an opportunistic pathogen that causes mucosal gastrointestinal (GI) candidiasis tightly associated with gut inflammatory status. The emergence of drug resistance, the side effects of currently available antifungals and the high frequency of recurrent candidiasis indicate that new and improved therapeutics are needed. Probiotics have been suggested as a useful alternative for the management of candidiasis. We demonstrated that oral administration of Lactobacillus gasseri LA806 alone or combined with Lactobacillus helveticus LA401 in Candida albicans-infected mice decrease the Candida colonization of the oesophageal and GI tract, highlighting a protective role for these strains in C. albicans colonization. Interestingly, the probiotic combination significantly modulates the composition of gut microbiota towards a protective profile and consequently dampens inflammatory and oxidative status in the colon. Moreover, we showed that L. helveticus LA401 and/or L. gasseri LA806 orient macrophages towards a fungicidal phenotype characterized by a C-type lectin receptors signature composed of Dectin-1 and Mannose receptor. Our findings suggest that the use of the LA401 and LA806 combination might be a promising strategy to manage GI candidiasis and the inflammation it causes by inducing the intrinsic antifungal activities of macrophages. Thus, the probiotic combination is a good candidate for managing GI candidiasis by inducing fungicidal functions in macrophages while preserving the GI integrity by modulating the microbiota and inflammation.
Published: 2021
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34. Abstract B77: GM102, a low fucosylated anti-Müllerian Hormone type II Receptor (AMHRII) antibody, promotes in vitro antitumoral activities of innate (macrophages) and adaptative (CD4+ and CD8+ T cells) immune cells

Author: Lydie Cassard, Mélanie Prat, Jean-François Prost, Olivier Dubreuil, Marie Salon, Thibault Allain, Jean-Marc Barret, Agnès Coste, Nathalie Van Acker, and Bernard Pipy
Subjects: Antibody-dependent cell-mediated cytotoxicity, Cancer Research, medicine.medical_treatment, Immunology, Immunotherapy, Biology, Acquired immune system, Immune system, Cancer research, medicine, biology.protein, Cytotoxic T cell, Antibody, CD8, CD80
Abstract: The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Its type 2 receptor, AMHRII, is selectively expressed in normal sexual organs in healthy adults but is also re-expressed in gynecologic cancers including ovarian tumors. Recently, AMHRII expression was also demonstrated in major cancers such as colorectal, non-small cell lung cancers and hepatocarcinoma. This set of consistent findings led to the development of GM102, a humanized glyco-engineered anti-AMHRII monoclonal antibody by GamaMabs Pharma. Following an extensive pharmacologic investigation as well as a regulatory toxicologic program in cynomolgus monkeys, clinical trials with GM102 were launched in 2016 and are currently ongoing. In vitro experiments using GM102 were performed to characterize more precisely its effect on human immune system. Macrophages from healthy donors were unstimulated or stimulated by M-CSF/IL-10 for conferring a TAM-like phenotype. These macrophages were co-cultured with SKOV3-AMHRII+ ovarian cancer target cells in the presence of GM102 before adding lymphocytes from the same donors. By this way, we demonstrate that GM102 opsonization of SKOV3-AMHRII+ tumor cells, in presence of unstimulated- or TAM-like macrophages, shifts the microenvironment toward a proinflammatory and antitumoral status (increase of IL-1β, IL- 12, TNF-α, IL-6 and decrease of IL-23, IL-10) and significantly promotes the macrophage-mediated ADCC and triggers antitumor activity. We also report that GM102 treatment orients the unstimulated- and TAM-like macrophages toward a population characterized by a strong expression of adaptive immune response co-stimulation marker, such as CD80, and induces a chemokine profile favorable to the recruitment of Th1 lymphocytes (increase of CCL-4, CCL-5, CXCL-9 and CXCL-10, as well as IL-12). Moreover, we show that GM102 treatment shifts Th1/Th2 balance of T CD4+ cells toward Th1 response and activates CD8+ T cells. Similar results were obtained with a COV434-AMHRII+ granulosa cell tumor cell line. Interestingly, preliminary analysis of blood samples and biopsies from patients treated by GM102 suggest, as well, a more global effect of GM102 on immune system than a sole involvement of ADCC/ADCP activity. In conclusion, all together these results reveal that GM102 antibody is able to trigger the antitumor activity of unstimulated macrophages and to reorient tumor-supporting macrophages to cytotoxic effectors. These macrophages are subsequently able to stimulate the antitumor adaptive immune system by inducing Th1 response of T CD4+ cells and by activating T CD8+ cells. Those mechanisms might participate to the sustained clinical benefit observed in advanced cancer patients treated with GM102. Citation Format: Thibault Allain, Marie Salon, Jean-Marc Barret, Mélanie Prat, Olivier Dubreuil, Nathalie Van Acker, Lydie Cassard, Bernard Pipy, Jean-François Prost, Agnès Coste. GM102, a low fucosylated anti-Müllerian Hormone type II Receptor (AMHRII) antibody, promotes in vitro antitumoral activities of innate (macrophages) and adaptative (CD4+ and CD8+ T cells) immune cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B77.
Published: 2020
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35. Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

Author: Mélissa Prat, Eliane Mery, Bettina Couderc, Renaud Mével, Hélène Leray, Benoît Thibault, Augustin Le Naour, Lise Lefèvre, Jean-Pierre Delord, Muriel Golzio, Léa Lemaitre, Agnès Coste, Gwenael Ferron, and Alejandra Martinez
Subjects: CXCL1, CXCL2, Immune system, Chemistry, Tumor progression, Mesenchymal stem cell, Cancer cell, Cancer research, Macrophage polarization, Ex vivo
Abstract: Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. We determine the mechanisms by which a naïve MSC could become a CA-MSC and characterize CA-MSCs. Ovarian tumor cells (OTC) trigger the transformation of MSCs to CA-MSCs expressing different pro-tumoral, genes and secreting high amounts of CXCR1/2 ligands (CXCL1, CXCL2 and IL-8) implicated in the chemoresistance of cancer cells. CXCR1/2 ligands can also inhibit the immune response against OTC. Indeed, through their released factors, CA-MSCs can trigger the differentiation of monocytes to pro-tumoral M2 phenotype macrophages known to promote the tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 functions and acquire an anti-tumoral phenotype. Both ex vivo and in vivo a CXCR1/2 inhibitor can sensitize OTC to carboplatin even in the presence of a pro-tumoral microenvironment. This inhibitor can circumvent the pro-tumoral effects of CA-MSCs. As high concentrations of CXCR1/2 ligands in blood from patients can be associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert chemoresistance.
Published: 2018
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36. nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in Apoe −/− Mice

Author: Nancy Geoffre, Anne Nègre-Salvayre, Agnès Coste, Emeline Recazens, Marie-Hélène Grazide, Paul Alayrac, Myriam Rouahi, Audrey Swiader, Tom Lallemand, Robert Salvayre, Nathalie Augé, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Inst Malad Metabol & Cardiovasc, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U1048 (I2CM), Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD)
Subjects: Male, 0301 basic medicine, Mice, Knockout, ApoE, NF-E2-Related Factor 2, [SDV]Life Sciences [q-bio], Anti-Inflammatory Agents, Aortic Diseases, Sphingomyelinase deficiency, Inflammation, Disease, Benzylidene Compounds, Mice, 03 medical and health sciences, medicine, Animals, Enzyme Inhibitors, Aorta, ComputingMilieux_MISCELLANEOUS, Aniline Compounds, sphingolipids, Apoe mice, Basic Sciences, business.industry, Endothelial Cells, Atherosclerosis, Sphingolipid, Plaque, Atherosclerotic, macrophages, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, RAW 264.7 Cells, Sphingomyelin Phosphodiesterase, 030104 developmental biology, Immunology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Macrophages, Peritoneal, Inflammation Mediators, medicine.symptom, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: Supplemental Digital Content is available in the text., Objective— Atherosclerosis is a chronic multifactorial and inflammatory disease of large and medium arteries and the leading cause of cardiovascular diseases worldwide. The aim of this study was to investigate whether and how the nSMase2 (type 2-neutral sphingomyelinase), a key enzyme of sphingolipid metabolism, may contribute to the development of atherosclerotic lesions. Approach and Results— The role of nSMase2 in atherosclerosis was investigated in Apoe−/−;Smpd3fro/fro mice, mutant for nSMase2, and in Apoe−/−;Smpd3+/+ mice intraperitoneally injected with GW4869, a pharmacological nSMase2 inhibitor. The defect or inhibition of nSMase2 resulted in a reduction of atherosclerotic lesions and a decrease in macrophage infiltration and lipid deposition, although cholesterolemia remained unchanged. nSMase2 inhibition decreased the inflammatory response of murine endothelial cells to oxLDL (oxidized low-density lipoprotein), as assessed by the significant reduction of MCP-1 (monocyte chemoattractant protein 1), ICAM-1 (intercellular adhesion molecule-1), and VCAM-1 (vascular cell adhesion molecule-1) mRNA expressions and macrophage recruitment. Likewise, in RAW264.7 or in macrophages isolated from Apoe−/−/Smpd3fro/fro or Apoe−/−/Smpd3+/+ mice stimulated by lipopolysaccharides, nSMase2 inhibition resulted in a decrease in the expression of inflammatory molecules. Mechanistically, the anti-inflammatory response resulting from nSMase2 inhibition involves Nrf2 (nuclear factor [erythroid-derived 2]-like 2 or NF-E2–related factor-2) activation in both endothelial cells and macrophages, as assessed by the lack of protective effect of GW4869 in endothelial cells silenced for Nrf2 by small interfering RNAs, and in lipopolysaccharide-stimulated macrophages issued from Nrf2-KO mice. Conclusions— The genetic deficiency or inhibition of nSMase2 strongly decreases the development of atherosclerotic lesions in Apoe−/− mice, by reducing inflammatory responses through a mechanism involving the Nrf2 pathway. Inhibitors of nSMase2 may, therefore, constitute a novel approach to slow down atherosclerosis progression.
Published: 2018
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37. Le P17, un nouveau peptide antimicrobien, favorise l’activité antifongique des macrophages via l’induction des récepteurs Mannose et Dectine-1 et contribue à la résolution d’une candidose digestive expérimentale

Author: Jérôme Leprince, José Bernad, Hélène Authier, Agnès Coste, Mouna Rahabi, Elsa Bonnafé, Mohammad Alaeddine, Michel Treilhou, Bernard Pipy, Mélissa Prat, Khaddouj Benmoussa, Lise Lefèvre, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biochimie et Toxicologie des Substances Bioactives (BTSB), Institut national universitaire Champollion [Albi] (INUC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Infectious Diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract: Article présenté dans un congrès à Toulouse les 30 et 31 mars 2017.; International audience; Malgré la connaissance croissante en ce qui concerne les propriétés immunomodulatrices des peptides antimicrobiens (AMP), leur impact sur la différenciation des macrophages et sur les fonctions microbicides associées est encore mal compris. Dans ce travail nous mettons en évidence l’activité immunomodulatrice du P17, un nouveau peptide antimicrobien isolé à partir du venin de fourmis. Nous montrons que ce peptide oriente la différenciation des macrophages dérivés de monocytes humains (h-MDMs) vers un phénotype particulier caractérisé à la fois par la surexpression des récepteurs mannose (RM) et Dectine-1, deux récepteurs lectine de type C (CLRs), et par une signature pro-inflammatoire. Dans cet état d’activation, les h-MDMs présentent une capacité accrue à reconnaître et internaliser C. albicans. Ces h-MDMs acquièrent aussi des fonctions fongicides puissantes via l’activation de la NADPH oxydase, enzyme nécessaire à la production d’espèces réactives de l’oxygène (ROS) et de l’inflammasome essentiel à la libération d’IL-1β. Nous démontrons également que la surexpression des récepteurs RM et Dectine-1 nécessite la mobilisation de l’acide arachidonique et la synthèse du leucotriène B4 (LTB4), essentiel à l’activation du récepteur nucléaire PPARg. Ainsi, la voie de signalisation LTB4/PPARg/MR-Dectine-1 est essentielle pour l’activité antifongique des h-MDMs activés par le P17. Enfin, nous avons également démontré in vivo que les souris traitées par le P17 infectées développent une infection gastro-intestinale à C. albicans moins sévère que les souris non traitées. En accord avec ces résultats, les macrophages isolés des souris traitées par le P17 ont une meilleure capacité à phagocyter C. albicans, à produire des ROS et à éliminer les levures ex vivo. Ces travaux mettent en évidence le P17 comme un activateur original de la réponse fongicide des macrophages et offrent de nouvelles perspectives thérapeutiques immunomodulatrices dans le domaine des maladies infectieuses.
Published: 2017
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38. First-in-human first-in-class phase I trial of murlentamab, an anti-Mullerian-hormone receptor II (AMHRII) monoclonal antibody acting through tumor-associated macrophage (TAM) engagement, as single agent and in combination with carboplatin (C) and paclitaxel (P) in AMHRII-expressing advanced/metastatic gynecological cancer patients (pts)

Author: François-Xavier Frenois, Christophe Le Tourneau, Ignace Vergote, Ahmad Awada, Jean-Pierre Delord, Marine Villard, Anne Floquet, Fanny Lemée, Elsa Kalbacher, Agnès Coste, Cyril Abdeddaim, Isabelle Tabah-Fisch, Alexandra Leary, Lydie Cassard, Olivier Lantz, Susana Banerjee, Isabelle Ray-Coquard, Michel Fabbro, Grégory Noël, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD)
Subjects: Cancer Research, medicine.drug_class, business.industry, macrophage (TAM), paclitaxel (P), [SDV]Life Sciences [q-bio], Tumor-associated macrophage, CD16, Monoclonal antibody, Carboplatin, 3. Good health, Cell membrane, chemistry.chemical_compound, medicine.anatomical_structure, Oncology, chemistry, Paclitaxel, anti-Mullerian-hormone receptor II (AMHRII), Anti-Müllerian hormone receptor, Cancer research, medicine, Macrophage, carboplatin (C), business, AMHRII-expressing advanced/metastatic gynecological cancer patients
Abstract: 2521 Background: Membranous expression of AMHRII is found in ~70% of gynecological tumors. Murlentamab (M) binds with high affinity both AMHRII (at cell membrane) and CD16 (on macrophage, via its low fucose Fc). M reprograms TAMs, restoring their antitumoral functions (phagocytosis) resulting in cytotoxic T cell reactivation. Methods: Pts with advanced/metastatic AMHRII-expressing ovarian, cervical or endometrial cancer with measurable disease and performance status ≤ 1 received M as single agent (SA) in 8 dose escalating and 2 expansion cohorts. Combination with CP was studied in 2 escalating cohorts. Safety, recommended dose determination, antitumor activity, pharmacodynamics (PD) effects (circulating immune cells and tumor microenvironment (TME) from paired biopsies) were assessed. Results: 68 heavily pretreated (median 4 prior lines) pts received M for 0.5 to 11 months (mo) (59 pts M SA and 9 pts M + CP). No dose limiting toxicity was reported. Most common toxicity was G1-2 asthenia (29 %). Eight pts (12%) had G ≥ 3 reversible toxicities (asthenia, nausea/vomiting, anorexia, arthralgia). No antidrug antibody was detected. One partial response (PR) was achieved with M SA in a granulosa pt. In CP combination, 4/9 pts (44%) responded to treatment (1 Complete Response and 3 PRs). Overall, 22/67 (33%) pts were progression-free at 4 mos. Among 17 pts treated ≥ 6 mos, 6/9 (67%) granulosa pts with M SA and 4/5 (80%) endometrium and cervix with CP combination had a longer PFS than under previous regimen. PD blood assessment of 25 pts treated with M SA showed an increase in classical monocytes, and T cells and neutrophils activation. Changes in TME under M will be presented. Conclusions: Murlentamab was very well tolerated, demonstrated immune PD effects and showed hints of antitumor activity. These results together with its innovative immunological mode of action support development of M in AMHRII-expressing cancers, in combination with chemotherapy or other immune oncology drugs. Clinical trial information: NCT02978755.
Published: 2019
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39. Biochemical and biophysical combined study of bicarinalin, an ant venom antimicrobial peptide

Author: Jérôme Leprince, Nathan Téné, Bernard Pipy, Agnès Coste, Aline Rifflet, Elsa Bonnafé, Laure Guilhaudis, Fanny Berger, Michel Treilhou, Isabelle Ségalas-Milazzo, Biochimie et Toxicologie des Substances Bioactives (BTSB), Institut national universitaire Champollion [Albi] (INUC), Université de Toulouse (UT)-Université de Toulouse (UT), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Urban Community of Albi, CNRS, Labex Synorg [UMR 6014], INSERM (U982), ANR-10-LABX-0025,CEBA,CEnter of the study of Biodiversity in Amazonia(2010), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)
Subjects: Models, Molecular, 0301 basic medicine, Antifungal Agents, Cell Membrane Permeability, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Protein Structure, Secondary, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Base Sequence, Biochemistry, Protein Structure, Secondary, Endocrinology, Salmonella, MESH: Insect Proteins, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, Lymphocytes, MESH: Cell Membrane Permeability, Candida albicans, MESH: Phylogeny, Peptide sequence, Cells, Cultured, Conserved Sequence, Phylogeny, Candida, chemistry.chemical_classification, Leishmania, MESH: Microbial Sensitivity Tests, MESH: Conserved Sequence, biology, Prepropeptide, MESH: Antimicrobial Cationic Peptides, Antimicrobial, Enterobacteriaceae, Anti-Bacterial Agents, 3. Good health, MESH: Cell Survival, Insect Proteins, Antimicrobial peptide, MESH: Models, Molecular, Half-Life, MESH: Half-Life, MESH: Cells, Cultured, Cell Survival, Antiparasitic, medicine.drug_class, Antiprotozoal Agents, MESH: Proteolysis, MESH: Ants, Microbial Sensitivity Tests, Ant venom, Microbiology, Lethal Dose 50, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Anti-Bacterial Agents, medicine, Animals, Humans, MESH: Ant Venoms, Amino Acid Sequence, MESH: Antiprotozoal Agents, Therapeutic index [TI], MESH: Humans, Base Sequence, Ant Venoms, Ants, biology.organism_classification, medicine.disease, MESH: Antifungal Agents, Cronobacter sakazakii, 030104 developmental biology, MESH: Lethal Dose 50, chemistry, Proteolysis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Lymphocytes, Antimicrobial Cationic Peptides
Abstract: International audience; We have recently characterized bicarinalin as the most abundant peptide from the venom of the ant Tetramorium bicarinatum. This antimicrobial peptide is active against Staphylococcus and Enterobacteriaceae. To further investigate the antimicrobial properties of this cationic and cysteine-free peptide, we have studied its antibacterial, antifungal and antiparasitic activities on a large array of microorganisms. Bicarinalin was active against fifteen microorganisms with minimal inhibitory concentrations ranging from 2 and 25μmolL(-1). Cronobacter sakazakii, Salmonella enterica, Candida albicans, Aspergilus niger and Saccharomyces cerevisiae were particularly susceptible to this novel antimicrobial peptide. Resistant strains of Staphylococcus aureus, Pseudomonas aeruginosa and C. albicans were as susceptible as the canonical strains. Interestingly, bicarinalin was also active against the parasite Leishmania infantum with a minimal inhibitory concentrations of 2μmolL(-1). The bicarinalin pre-propeptide cDNA sequence has been determined using a combination of degenerated primers with RACE PCR strategy. Interestingly, the N-terminal domain of bicarinalin pre-propeptide exhibited sequence similarity with the pilosulin antimicrobial peptide family previously described in the Myrmecia venoms. Moreover, using SYTOX green uptake assay, we showed that, for all the tested microorganisms, bicarinalin acted through a membrane permeabilization mechanism. Two dimensional-NMR experiments showed that bicarinalin displayed a 10 residue-long α-helical structure flanked by two N- and C-terminal disordered regions. This partially amphipathic helix may explain the membrane permeabilization mechanism of bicarinalin observed in this study. Finally, therapeutic value of bicarinalin was highlighted by its low cytotoxicity against human lymphocytes at bactericidal concentrations and its long half-life in human serum which was around 15h.
Published: 2016
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40. Aqueous extract of Vitex trifolia L. (Labiatae) inhibits LPS-dependent regulation of inflammatory mediators in RAW 264.7 macrophages through inhibition of Nuclear Factor kappa B translocation and expression

Author: Dominique Laurent, Serge Pauillac, Mariko Matsui, Bernard Pipy, Shilpa Kumar-Roiné, Agnès Coste, Minou Adib-Conquy, Institut Pasteur de Nouvelle-Calédonie, Réseau International des Instituts Pasteur (RIIP), Cytokines et Inflammation, Institut Pasteur [Paris], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD), Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, IFR50-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Bactéries anaérobies et Toxines, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR50, Institut Pasteur [Paris] (IP), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-IFR50
Subjects: Lipopolysaccharides, Chemokine, Lipopolysaccharide, Anti-Inflammatory Agents, Gene Expression, Vitex, Nuclear factor kappa B, Mice, chemistry.chemical_compound, 0302 clinical medicine, Vitex trifolia, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Discovery, Gene expression, Chemokine CCL3, 2. Zero hunger, 0303 health sciences, biology, Traditional medicine, Chemistry, NF-kappa B, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Cytokines, Inflammation Mediators, Chemokines, Anti-inflammatory activity, 03 medical and health sciences, In vivo, Animals, RNA, Messenger, 030304 developmental biology, Inflammation, Pharmacology, Cyclooxygenase 2 Inhibitors, Plant Extracts, Macrophages, Transcription Factor RelA, NF-kappa B p50 Subunit, Biological Transport, COX-2, biology.organism_classification, Molecular biology, Chemokine CXCL10, Cyclooxygenase 2, Apoptosis, biology.protein, Phytotherapy
Abstract: Ethnopharmacological relevance: Vitex trifolia L. (Labiatae), a widespread tree found from the Asia-Pacific to the east Africa regions is used in the traditional medicine of the Pacific islands to treat inflammatory-associated conditions. Aim of the study: We herein evaluated its in vitro regulatory effects on the expression profile of lipopolysaccharide (LPS)-induced inflammatory genes focusing on regulation of chemokines C-X-C motif 10 (CXCL-10) and C-C motif ligand 3 (CCL-3) and cyclo-oxygenase (COX)-2. Furthermore, the plant effect on the LPS-mediated activation of Nuclear Factor kappa B (NF-kappa B) was also studied. Materials and methods: Aqueous extract of Vitex trifolia leaves was prepared and evaluated for its effect on LPS-induced stress and toxicity-related genes in RAW 264.7 macrophage cells using RT2 Profiler Polymerase Chain Reaction (PCR) Array System. Effects of the extract on LPS-induced chemokines CCL-3 and CXCL-10, COX-2, and NF-kappa B p50 and p65 mRNA levels were also studied using Reverse Transcription quantitative PCR (RT-qPCR) technique. Translocation of the nuclear factor was further assessed by measuring its nuclear p65 subunit via an ELISA-based TransAM method. Results: Vitex trifolia extract at 5000 mu g/ml exerted a significant inhibitory effect on the expression of various LPS-induced inflammatory genes in RAW 264.7 cells after 8 h of incubation time. Using RT-qPCR, this anti-inflammatory effect was further confirmed by significant inhibition of CCL-3 and CXCL-10 mRNA production in LPS-stimulated RAW 264.7 cells upon treatment with 2500 mu g/ml of Vitex trifolia extract. Furthermore, the inhibitory activity of this plant on LPS-induced COX-2 mRNA was also observed at a concentration of 2500 mu g/ml in a time-dependent manner. TransAM assays showed that LPS-induced NF-kappa B translocation was also inhibited by Vitex trifolia extract even at a concentration of extract as low as 250 mu g/ml. RT-qPCR assays showed that aqueous extract of Vitex trifolia leaves had a significant inhibitory activity on LPS-induced p50 mRNA synthesis. Interestingly, however, no effect on p65 subunit mRNA expression was observed. Moreover, PCR array analysis showed that LPS-induced inflammatory and apoptosis genes under NF-kappa B control are also repressed by the extract. Conclusion: The anti-inflammatory properties of Vitex trifolia extract seem associated with inhibition of NF-kappa B translocation through a reduction in the expression level of NF-kappa B p50 but interestingly not p65 subunit mRNA. The regulatory effects of Vitex trifolia on NF-kappa and consequently on inflammation mediators such as chemokines CCL-3 and CXCL-10, and COX-2 provide new evidence of its efficacy and emphasise its high potential therapeutic value. However, further in vivo experiments are still required to validate its utilization as a remedy against inflammatory diseases.
Published: 2012
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41. A first-in-human study of monoclonal antibody GM102 in patients with anti-Mullerian-hormone-receptor II (AMHRII) positive gynecological cancers

Author: Andrea Varga, Francesco Ricci, Philippe Aftimos, Jean-Pierre Delord, Agnès Coste, Guillaume Bataillon, Grégory Noël, Carlos Gomez-Roca, Isabelle Tabah-Fisch, Jean-François Prost, Alexandra Leary, Anne Vincent Salomon, Lydie Cassard, Nathalie Van Acker, Christophe Le Tourneau, Bérengère Jean, Christiane Jungels, Olivier Lantz, Ahmad Awada, and Isabelle Ray-Coquard
Subjects: 0301 basic medicine, endocrine system, Cancer Research, endocrine system diseases, urogenital system, medicine.drug_class, Mullerian Ducts, business.industry, Embryo, First in human, Monoclonal antibody, female genital diseases and pregnancy complications, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, Cell surface receptor, 030220 oncology & carcinogenesis, Anti-Müllerian hormone receptor, medicine, Cancer research, In patient, business
Abstract: 5542Background: AMH and its membrane receptor AMHRII induce regression of Mullerian ducts in the male embryo. AMHRII is constitutively expressed in ovarian granulosa tumors (GCT) and re-expressed i...
Published: 2018
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42. Uncaria tomentosa increases ROS production and improves mRNA expression of Dectine-1 receptor in human macrophages

Author: Ivan, Lozada-Requena, Jose, Bernad, Melissa, Prat, Mohamad, Alaeddine, Khaddouj, Benmoussa, César, Núñez, JOSE, AGUILAR, Bernard, Pipy, and Agnès, Coste
Subjects: Immunology, Immunology and Allergy
Published: 2015
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43. Leishmanicidal compounds and potent PPARγ activators from Renealmia thyrsoidea (Ruiz & Pav.) Poepp. & Endl

Author: Denis Castillo, Michel Sauvain, Geneviève Bourdy, Billy Cabanillas, Bernard Pipy, Céline Valadeau, Agnès Coste, Jorge Arevalo, David Olagnier, Anne-Cécile Le Lamer, Nicolas Fabre, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Laboratorios de Investigación y Desarrollo (LID), Universidad Peruana Cayetano Heredia (UPCH), DSF-IRD (BST), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)
Subjects: Male, Leishmanicidal activity, Renealmia thyrsoidea, PPARγ, [SDV]Life Sciences [q-bio], Leishmania mexicana, Antiprotozoal Agents, Real-Time Polymerase Chain Reaction, Mice, Medicinal plants, Zingiberaceae, Drug Discovery, Peru, Animals, Humans, Axenic, Cytotoxicity, Amastigote, Diarylheptanoids, Pharmacology, Mice, Inbred BALB C, biology, Plant Extracts, Macrophages, biology.organism_classification, 3. Good health, Rhizome, PPAR gamma, Plant Leaves, Phytochemical, Biochemistry, Medicine, Traditional, Mannose receptor
Abstract: International audience; Ethnopharmacological relevance: Leaves and rhizomes of Renealmia thyrsoidea (Ruiz & Pav.) Poepp. & Endl. traditionally used in the Yanesha pharmacopoeia to treat skin infections such as leishmaniasis ulcers, or to reduce fever were chemically investigated to identify leishmanicidal compounds, as well as PPARγ activators.Methods: Compounds were isolated through a bioassay-guided fractionation and their structures were determined via detailed spectral analysis. The viability of Leishmania amazonensis axenic amastigotes was assessed by the reduction of tetrazolium salt (MTT), the cytotoxicity on macrophage was evaluated using trypan blue dye exclusion method, while the percentage of infected macrophages was determined microscopically in the intracellular macrophage-infected assay. The CD36, mannose receptor (MR) and dectin-1 mRNA expression on human monocytes-derived macrophages was evaluated by quantitative real-time PCR.Results: Six sesquiterpenes (1-6), one dihydrobenzofuranone (7) and four flavonoids (8-11) were isolated from the leaves. Alongside, two flavonoids (12-13) and five diarylheptanoids (14-18) were identified in the rhizomes. Leishmanicidal activity against Leishmania amazonensis axenic amastigotes was evaluated for all compounds. Compounds 6, 7, and 11, isolated from the leaves, showed to be the most active derivatives. Diarylheptanoids 14-18 were also screened for their ability to activate PPARγ nuclear receptor in macrophages. Compounds 17 and 18 bearing a Michael acceptor moiety strongly increased the expression of PPARγ target genes such as CD36, Dectin-1 and mannose receptor (MR), thus revealing interesting immunomodulatory properties.Conclusions: Phytochemical investigation of Renealmia thyrsoidea has led to the isolation of leishmanicidal compounds from the leaves and potent PPARγ activators from the rhizomes. These results are in agreement with the traditional uses of the different parts of Renealmia thyrsoidea.
Published: 2014
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44. Protolichesterinic acid derivatives: α-methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors

Author: Isabelle Rouaud, Agnès Coste, Anne-Cécile Le Lamer, Bernard Pipy, Nicolas Gouault, Joël Boustie, Hélène Authier, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD)
Subjects: PPARγ, NF-E2-Related Factor 2, Stereochemistry, Protolichesterinic acid, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Biochemistry, Nrf2, Lactones, Mice, Structure-Activity Relationship, chemistry.chemical_compound, 4-Butyrolactone, Cell Line, Tumor, Drug Discovery, Animals, Humans, Moiety, Potency, [CHIM]Chemical Sciences, Methylene, Cytotoxicity, Molecular Biology, Transcription factor, Cell Proliferation, Dose-Response Relationship, Drug, Molecular Structure, Macrophages, Organic Chemistry, respiratory system, 3. Good health, PPAR gamma, α-Methylene-γ-lactones, chemistry, Michael reaction, Molecular Medicine, Organic synthesis, Drug Screening Assays, Antitumor, Signal transduction, Michael acceptor
Abstract: International audience; PPARγ and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of α,β-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPARγ and Nrf2 activation evaluation. Among them, two α-methylene-γ-lactones were identified as potent dual activators of PPARγ and Nrf2 in macrophages.
Published: 2014
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45. Kinetics of monocyte subpopulations during experimental cerebral malaria and its resolution in a model of late chloroquine treatment

Author: Jade Royo, Aissata Camara, Benedicte Bertrand, Philippe Batigne, Agnes Coste, Bernard Pipy, Agnes Aubouy, the NeuroCM Group, Dissou Affolabi, Jules Alao, Daniel Ajzenberg, Linda Ayédadjou, Gwladys Bertin, Bibiane Biokou, Farid Boumédiène, Josselin Brisset, Michel Cot, Jean-Eudes Degbelo, Philippe Deloron, Ida Dossou-Dagba, Latifou Dramane, Jean François Faucher, Sandrine Houzé, Sayeh Jafari-Guemouri, Claire Kamaliddin, Elisée Kinkpé, Anaïs Labrunie, Yélé Ladipo, Thomas Lathiere, Achille Massougbodji, Audrey Mowendabeka, Jade Papin, Pierre-Marie Preux, Marie Raymondeau, Darius Sossou, Brigitte Techer, Bertin Vianou, and Laurence Watier
Subjects: cerebral malaria (CM), mice, monocyte, brain, spleen, blood, Microbiology, QR1-502
Abstract: Cerebral malaria (CM) is one of the most severe forms of malaria and is a neuropathology that can lead to death. Monocytes have been shown to accumulate in the brain microvasculature at the onset of neurological symptoms during CM. Monocytes have a remarkable ability to adapt their function to their microenvironment from pro-inflammatory to resolving activities. This study aimed to describe the behavior of monocyte subpopulations during infection and its resolution. C57BL/6 mice were infected with the Plasmodium berghei ANKA strain and treated or not with chloroquine (CQ) on the first day of the onset of neurological symptoms (day 6) for 4 days and followed until day 12 to mimic neuroinflammation and its resolution during experimental CM. Ly6C monocyte subpopulations were identified by flow cytometry of cells from the spleen, peripheral blood, and brain and then quantified and characterized at different time points. In the brain, the Ly6Cint and Ly6Clow monocytes were associated with neuroinflammation, while Ly6Chi and Ly6Cint were mobilized from the peripheral blood to the brain for resolution. During neuroinflammation, CD36 and CD163 were both involved via splenic monocytes, whereas our results suggest that the low CD36 expression in the brain during the neuroinflammation phase was due to degradation. The resolution phase was characterized by increased expressions of CD36 and CD163 in blood Ly6Clow monocytes, a higher expression of CD36 in the microglia, and restored high expression levels of CD163 in Ly6Chi monocytes localized in the brain. Thus, our results suggest that increasing the expressions of CD36 and CD163 specifically in the brain during the neuroinflammatory phase contributes to its resolution.
Published: 2022
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46. Extracts of Crinum latifolium inhibit the cell viability of mouse lymph oma cell line EL4 and induce activation of anti-tumour activity of macrophages in vitro

Author: Bernard Pipy, Bach-Hue T. Vo, Françoise Nepveu, Karine Reybier, Agnès Coste, Hoang-Yen T. Nguyen, José Bernad, Mohamad Alaeddine, Lac-Thuy H. Nguyen, Children's Hospital No. 2 [Ho Chi Minh City], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD)
Subjects: MTT, polymerase chain reaction, [SDV]Life Sciences [q-bio], M1, Crinum latifolium, Mice, 0302 clinical medicine, Drug Discovery, Cytotoxicity, reactive oxygen species, 0303 health sciences, biology, Cell Differentiation, ROS, peripheral blood mononuclear cells, 3. Good health, PCR, Biochemistry, Vietnam, 030220 oncology & carcinogenesis, CL, Crinum latifolium L, Cell Survival, 3-(4, Macrophage polarization, Radical scavenger, Immunomodulation, 03 medical and health sciences, Alkaloids, Cell Line, Tumor, Animals, Humans, MTT assay, 5-dimethylthiazol-2-yl)-2, Viability assay, 2-diphenyl-1-picrylhydrazyl, 5-diphenyltetrazolium bromide, 030304 developmental biology, Cell Proliferation, Pharmacology, Medicine, East Asian Traditional, Plant Extracts, Macrophages, PBMC, biology.organism_classification, Antineoplastic Agents, Phytogenic, In vitro, Coculture Techniques, Plant Leaves, Cell culture, Cancer cell, Crinum, Ethnopharmacology, Macrophages, Peritoneal, classically activated macrophages, DPPH
Abstract: Ethnopharmacological relevance Crinum latifolium L. (CL) leaf extracts have been traditionally used in Vietnam and are now used all over the world for the treatment of prostate cancer. However, the precise cellular mechanisms of the action of CL extracts remain unclear. Aim of the study To examine the effects of CL samples on the anti-tumour activity of peritoneal murine macrophages. Materials and methods The properties of three extracts (aqueous, flavonoid, alkaloid), one fraction (alkaloid), and one pure compound (6-hydroxycrinamidine) obtained from CL, were studied (i) for redox capacities (DPPH and bleaching beta-carotene assays), (ii) on murine peritoneal macrophages (MTT assay) and on lymphoma EL4-luc2 cells (luciferine assay) for cytotoxicity, (iii) on macrophage polarization (production of ROS and gene expression by PCR), and (iv) on the tumoricidal functions of murine peritoneal macrophages (lymphoma cytotoxicity by co-culture with syngeneic macrophages). Results The total flavonoid extract with a high antioxidant activity (IC 50 =107.36 mg/L, DPPH assay) showed an inhibitory action on cancer cells. Alkaloid extracts inhibited the proliferation of lymphoma cells either by directly acting on tumour cells or by activating of the tumoricidal functions of syngeneic macrophages. The aqueous extract induced mRNA expression of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6) indicating differentiation of macrophages into pro-inflammatory M1 polarized macrophages. The total flavonoid, alkaloid extracts and an alkaloid fraction induced the expression of the formyl peptide receptor (FPR) on the surface of the polarized macrophages that could lead to the activation of macrophages towards the M1 phenotype. Aqueous and flavonoid extracts enhanced NADPH quinine oxido-reductase 1 (NQO1) mRNA expression in polarized macrophages which could play an important role in cancer chemoprevention. All the samples studied were non-toxic to normal living cells and the pure alkaloid tested, 6-hydroxycrinamidine, was not active in any of the models investigated. Conclusions Our results indicate that CL extracts and alkaloid fraction (but not pure 6-hydroxycrinamidine) inhibit the proliferation of lymphoma cells in multiple pathways. Our results are in accordance with traditional usage and encourage further studies and in vivo assays.
Published: 2013
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47. The C-type Lectin Receptors Dectin-1, MR, and SIGNR3 Contribute Both Positively and Negatively to the Macrophage Response to Leishmania infantum

Author: Carine Duval, Johan Auwerx, Christophe Dardenne, Jean Loup Lemesre, Alexis Valentin, Hélène Authier, Bernard Pipy, Etienne Meunier, David Olagnier, Lise Lefèvre, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Agnès Coste, José Bernad, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Focal Area Infection Biology, Biozentrum, University of Basel (Unibas), Division of Infectious Diseases, University of South Florida (USF), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona (UB), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de la Signalisation et de la Différenciation des Macrophages, Institution Louis Bugnard, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, MESH: Mannose-Binding Lectins / metabolism, [SDV]Life Sciences [q-bio], Interleukin-1beta, MESH: Leishmaniasis, Visceral / immunology, Antigens, CD/metabolism, Macrophages/immunology, MESH: Mice, Knockout, MESH: Antigens, CD / metabolism, MESH: Protein-Tyrosine Kinases / metabolism, Caspase 1/metabolism, Mice, 0302 clinical medicine, MESH: Leishmania infantum / immunology, MESH: Caspase 1 / metabolism, C-type lectin, MESH: RNA, Small Interfering, MESH: Interleukin-1beta / antagonists & inhibitors, Macrophage, Immunology and Allergy, MESH: Animals, MESH: Leishmaniasis, Visceral / parasitology, MESH: Receptors, Cell Surface / metabolism, Leishmania infantum, RNA, Small Interfering, Receptor, MESH: NADPH Oxidases / metabolism, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Arachidonic Acid, biology, Effector, Caspase 1, Intracellular Signaling Peptides and Proteins, Protein-Tyrosine Kinases, MESH: Macrophages / immunology, 3. Good health, Cell biology, MESH: Leukotriene B4 / antagonists & inhibitors, Infectious Diseases, Intracellular Signaling Peptides and Proteins/metabolism, NADPH Oxidases/metabolism, Leishmaniasis, Visceral, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA Interference, Signal transduction, Interleukin-1beta/antagonists & inhibitors, Mannose receptor, Mannose Receptor, Signal Transduction, MESH: Cells, Cultured, MESH: Reactive Oxygen Species / metabolism, Immunology, MESH: RNA Interference, Receptors, Cell Surface, Leukotriene B4, Arachidonic Acid/metabolism, MESH: Syk Kinase, 03 medical and health sciences, Antigens, CD, Reactive Oxygen Species/metabolism, MESH: Mice, Inbred C57BL, parasitic diseases, MESH: Arachidonic Acid / metabolism, Animals, Humans, Syk Kinase, Lectins, C-Type, Lectins, C-Type/immunology, MESH: Interleukin-1beta / metabolism, Receptors, Cell Surface/metabolism, Mannose-Binding Lectins/metabolism, MESH: Mice, 030304 developmental biology, MESH: Humans, Leishmania infantum/immunology, Macrophages, NADPH Oxidases, biology.organism_classification, Leishmania, MESH: Mannose Receptor, Leishmaniasis, Visceral/immunology, Protein-Tyrosine Kinases/metabolism, MESH: Lectins, C-Type / metabolism, Mice, Inbred C57BL, MESH: Lectins, C-Type / immunology, Mannose-Binding Lectins, Leukotriene B4/antagonists & inhibitors, Reactive Oxygen Species, MESH: Intracellular Signaling Peptides and Proteins / metabolism, 030215 immunology
Abstract: International audience; Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in vivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1β secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1β axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis.
Published: 2013
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48. Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation

Author: Emmanuel Flahaut, Bernard Pipy, David Olagnier, Etienne Meunier, Lise Lefèvre, Maryse Beraud, Christophe Dardenne, José Bernad, Hélène Authier, Agnès Coste, Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-IFR50, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre interuniversitaire de recherche et d'ingenierie des matériaux (CIRIMAT), Centre National de la Recherche Scientifique - CNRS (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut de Recherche pour le Développement - IRD (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), IFR50-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), and Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Subjects: Interleukin-1beta/immunology, Double-walled carbon nanotubes, Materials science, Inflammasomes/immunology, Inflammasomes, Phagocytosis, Interleukin-1beta, Biomedical Engineering, Pharmaceutical Science, Medicine (miscellaneous), Médecine humaine et pathologie, Bioengineering, Inflammation, 02 engineering and technology, Carbon nanotube, Monocytes, law.invention, [SPI.MAT]Engineering Sciences [physics]/Materials, 03 medical and health sciences, law, Monocytes/drug effects, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Nlrp3 inflammasome, Materials Testing, medicine, Humans, General Materials Science, Secretion, Inflammation Mediators/immunology, Receptor, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Nanotubes, Carbon, Inflammasome, 021001 nanoscience & nanotechnology, Cell biology, Micro et nanotechnologies/Microélectronique, IL-1β, Human monocytes, Immunology, Molecular Medicine, Efflux, NLRP3 inflammasome activation, medicine.symptom, Inflammation Mediators, 0210 nano-technology, medicine.drug
Abstract: Because of their outstanding physical properties, carbon nanotubes (CNTs) are promising new materials in the field of nanotechnology. It is therefore imperative to assess their adverse effects on human health. Monocytes/macrophages that recognize and eliminate the inert particles constitute the main target of CNTs. In this article, we report our finding that double-walled CNTs (DWCNTs) synergize with Tolllike receptor agonists to enhance IL-1β release in human monocytes. We show that DWCNTs–induced IL-1β secretion is exclusively linked to caspase-1 and to Nlrp3 inflammasome activation in human monocytes. We also establish that this activation requires DWCNTs phagocytosis and potassium efflux, but not reactive oxygen specied (ROS) generation. Moreover, inhibition of lysosomal acidification or cathepsin-B activation reduces DWCNT-induced IL-1β secretion, suggesting that Nlrp3 inflammasome activation occurs via lysosomal destabilization. Thus, DWCNTs present a health hazard due to their capacity to activate Nlrp3 inflammasome, recalling the inflammation caused by asbestos and hence demonstrating that they should be used with caution. From the Clinical Editor: This is a very important biosafety/toxicity study regarding double walled carbon nanotubes. The investigators demonstrate that such nanotubes do represent a health hazard due to their capacity to activate Nlrp3 inflammasome, resembling the inflammation caused by asbestos. While further study of this phenomenon is definitely needed, the above findings clearly suggest that special precautions need to be taken when applying these nanoparticles in human disease research.
Published: 2012
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49. Nrf2, a PPARγ Alternative Pathway to Promote CD36 Expression on Inflammatory Macrophages: Implication for Malaria

Author: Etienne Meunier, Antoine Berry, Lise Lefèvre, Bernard Pipy, Françoise Benoit-Vical, Rose-Anne Lavergne, Christophe Dardenne, David Olagnier, Bernhard Ryffel, Agnès Coste, and Agnès Aubouy
Subjects: lcsh:Immunologic diseases. Allergy, CD36 Antigens, Erythrocytes, NF-E2-Related Factor 2, Phagocytosis, CD36, Immunology, Plasmodium falciparum, Peroxisome proliferator-activated receptor, Down-Regulation, Inflammation, Mice, Transgenic, Microbiology, environment and public health, Mice, Downregulation and upregulation, Virology, parasitic diseases, Genetics, medicine, Animals, Humans, Malaria, Falciparum, Molecular Biology, Transcription factor, lcsh:QH301-705.5, Biology, chemistry.chemical_classification, biology, Macrophages, respiratory system, biology.organism_classification, Cell biology, Mice, Inbred C57BL, PPAR gamma, chemistry, Nuclear receptor, lcsh:Biology (General), biology.protein, Medicine, Parasitology, Female, medicine.symptom, lcsh:RC581-607, Research Article
Abstract: CD36 is the major receptor mediating nonopsonic phagocytosis of Plasmodium falciparum-parasitized erythrocytes by macrophages. Its expression on macrophages is mainly controlled by the nuclear receptor PPARγ. Here, we demonstrate that inflammatory processes negatively regulate CD36 expression on human and murine macrophages, and hence decrease Plasmodium clearance directly favoring the worsening of malaria infection. This CD36 downregulation in inflammatory conditions is associated with a failure in the expression and activation of PPARγ. Interestingly, using siRNA mediating knock down of Nrf2 in macrophages or Nrf2- and PPARγ-deficient macrophages, we establish that in inflammatory conditions, the Nrf2 transcription factor controls CD36 expression independently of PPARγ. In these conditions, Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and CD36-mediated Plasmodium phagocytosis. These results were confirmed in human macrophages and in vivo where only Nrf2 activators improve the outcome of severe malaria. Collectively, this report highlights that the Nrf2 transcription factor could be an alternative target to PPARγ in the control of severe malaria through parasite clearance., Author Summary Severe and fatal malaria is still increasing both in incidence and in its resistance to antimalarial agents. The improved understanding of immune mechanisms mediating Plasmodium elimination might therefore offer a complementary way to conventional therapeutic interventions. The main host innate immune defense mechanism against Plasmodium falciparum is the engulfment by macrophages through CD36, the macrophage receptor recognizing infected erythrocytes. The up-regulation of CD36 on macrophages therefore represents an alternative way to favor parasite clearance during infection. Severe malaria infection is associated with an excessive production of proinflammatory markers and an inability to control parasite proliferation. We demonstrate here that malaria-induced inflammation down regulates CD36 expression on macrophages and favors the worsening of malaria infection. The conventional way to promote CD36 expression through PPARγ nuclear receptor is inefficient under malaria inflammatory processes. Interestingly, we establish that the Nrf2 transcription factor may substitute PPARγ to promote CD36 expression and its associated functions in inflammatory conditions. As a consequence, only Nrf2 but not PPARγ activators improve the outcome of severe malaria in vivo. This paper which highlights a new area of application for Nrf2 activators in infectious diseases, heralds the emergence of a new therapeutic strategy against severe malaria.
Published: 2011

50. Cartographie de l’expression des différentes isoenzymes de la monoxyde d’azote synthase dans l’hyperplasie bénigne prostatique

Author: Maxime Thoulouzan, M. Ala Eddine, X. Gamé, Louis Bujan, P. Njomnang Soh, M. Soulié, Nicolas Doumerc, Hélène Authier, Pascal Rischmann, F. Zaidi, P. Roulette, Catherine Mazerolles, E. Huyghe, Agnès Coste, and B. Malavaud
Subjects: Gynecology, medicine.medical_specialty, business.industry, Urology, Medicine, business
Abstract: Objectifs Etudier la repartition des trois monoxide d’azote synthase (NOS) : nNOS, iNOS, eNOS entre les zones peripherique (ZP) et transitionnelle (ZT) chez des patients ayant une hyperplasie benigne prostatique (HBP). Methodes Une etude prospective unicentrique a ete realisee sur les tissus non tumoraux des ZP et ZT de pieces de prostatectomie radicale d’hommes ayant une HBP. Les patients ayant eu des traitements modifiant la structure de la glande ont ete exclus. Une etude de l’expression des 3 isoenzymes a ete menee par qRT-PCR dans chaque zone. L’inflammation histologique aigue et chronique a ete scoree. Chaque patient a repondu en preoperatoire aux questionnaires symptomatiques IPSS, USP et IIEF5. Le critere de jugement principal etait l’expression des differentes NOS au sein de la prostate par qRT-PCR. Resultats Seize des 85 patients ayant eu une prostatectomie totale entre le 01/11/13 et le 01/05/14 ont ete inclus. La qRT-PCR a montre une expression des trois isoenzymes dans la ZP et la ZT. Leur expression etait comparable au sein de la ZT, mais dans la ZP, il existait significativement moins de nNOS que de eNOS (p = 0,0017) et de iNOS (p = 0,0016). Il existait une correlation inverse entre l’expression de eNOS au sein de la ZP et le score IPSS (r = –0,5414), le score de qualite de vie (r = –0,5613) et une correlation positive avec l’IIEF (r = 0,5680). En revanche, aucune difference d’expression des NOS n’a ete trouvee entre la ZP et la ZT, et il n’y avait pas de relation entre expression des NOS et poids prostatique, scores USP dysurie et hyperactivite vesicale. Conclusion Les trois NOS etaient exprimees dans la ZP et la ZT. Dans la ZP, l’expression de la nNOS etait plus faible que celle de eNOS et de iNOS. De plus, il y avait une correlation inverse entre l’expression de eNOS au sein de la ZP et les symptomes urinaires et une correlation positive avec l’IIEF.
Published: 2014
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