125 results on '"Dumoutier L"'
Search Results
2. Les agonistes du récepteur du GLP-1 améliorent-ils le psoriasis chez des diabétiques de type 2 ? Données préliminaires
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Preumont, V., Baeck, M., Marot, L., Dumoutier, L., and Buysschaert, M.
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- 2014
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3. Correction: Interleukin-22-deficiency and microbiota contribute to the exacerbation of Toxoplasma gondii-induced intestinal inflammation
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Couturier-Maillard, A, Froux, N, Piotet-Morin, J, Michaudel, C, Brault, L, Le Bérichel, J, Sénéchal, A, Robinet, P, Chenuet, P, Jejou, S, Dumoutier, L, Renauld, J C, Iovanna, J, Huber, S, Chamaillard, M, Quesniaux, V F J, Sokol, H, and Ryffel, B
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- 2019
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4. Cytokine-Storm-Induced Coagulopathy In Critical COVID-19 and Septic Shock Patients: Head-to-Head Comparison
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Martin M, Ginion A, Hélène Haguet, Poortere Jd, Bodart J, L. Gatto, Daumerie A, Montiel, Dievoet Mv, Jonathan Douxfils, Christophe Beauloye, Gruson D, Bouzin C, Luc Bertrand, Sandrine Horman, Mélanie Dechamps, Gerard L, Pierre-François Laterre, M. Derive, Laure Morimont, Jolly L, Octave M, Diego Castanares-Zapatero, Dumoutier L, Pirotton L, Campion A, and Robaux
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ARDS ,medicine.medical_specialty ,Septic shock ,business.industry ,medicine.medical_treatment ,medicine.disease ,Clinical trial ,Internal medicine ,Fibrinolysis ,medicine ,Coagulopathy ,Platelet activation ,Cytokine storm ,Prospective cohort study ,business - Abstract
Background: A cytokine-storm-induced coagulopathy has been described in both critical COVID-19 and septic shock. Improving the understanding of the critical COVID-19 pathophysiology could help in finding new therapeutic targets already explored in the treatment of septic shock. Methods: This prospective observational was conducted between February 1, 2019, and June 1, 2020. Consecutive adult patients admitted to ICU for critical COVID-19 with acute respiratory distress syndrome (ARDS) (n=22), septic shock (n=48) and matched control patients (n=48) were enrolled. A between-group comparison of lung histopathology, clinical characteristics and outcomes and key plasmatic soluble biomarkers of inflammation and coagulopathy was performed. Findings: The histopathological findings showed microthrombi with NETosis in both COVID-19- and septic shock-related ARDS. In the prospective cohort, the critical COVID-19 patients exhibited a prolonged ICU length-of-stay, less organ failure, no sepsis-induced coagulopathy, a higher level of soluble tissue factor (106±57 versus 60±28pg/mL for septic shock, p
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- 2021
5. Interleukin-22 Deficiency Accelerates the Rejection of Full Major Histocompatibility Complex-Disparate Heart Allografts
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Kapessidou, P., Poulin, L., Dumoutier, L., Goldman, M., Renauld, J.-C., and Braun, M.Y.
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- 2008
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6. Improvement of psoriasis during glucagon-like peptide-1 analogue therapy in type 2 diabetes is associated with decreasing dermal γδ T-cell number: a prospective case-series study
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Buysschaert, M., Baeck, M., Preumont, V., Marot, L., Hendrickx, E., Van Belle, A., and Dumoutier, L.
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- 2014
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7. Correlations between disease activity, autoimmunity and biological parameters in patients with chronic spontaneous urticaria
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de Montjoye, L., primary, Darrigade, A.S., additional, Gimenez Arnau, A., additional, Herman, A., additional, Dumoutier, L., additional, and Baeck, M., additional
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- 2021
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8. IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes
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Dumoutier, L, Van Roost, E, Ameye, G, Michaux, L, and Renauld, J-C
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- 2000
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9. P337 Rémission prolongée du psoriasis chez un patient diabétique traité par exenatide
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Preumont, V., primary, Baeck, M., additional, Dumoutier, L., additional, and Buysschaert, M., additional
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- 2014
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10. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line - Pathways that are shared with and distinct from IL-10
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Lejeune, D, Dumoutier, L, Constantinescu, S, Kruijer, W, Schuringa, JJ, Renauld, JC, and Stem Cell Aging Leukemia and Lymphoma (SALL)
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ALPHA-INTERFERON ,INDUCIBLE FACTOR ,ACUTE-PHASE RESPONSE ,FUNCTIONAL-CHARACTERIZATION ,RECEPTOR COMPLEXES ,DNA-BINDING ,SERINE PHOSPHORYLATION ,SIGNALING PATHWAY ,TRANSCRIPTIONAL ACTIVATION ,IL-TIF - Abstract
IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK,PK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.
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- 2002
11. PO5 Évolution clinique et histologique de lésions psoriasiques sous traitement de moyenne durée par analogues du GLP-1 chez des diabétiques de type 2
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Preumont, V., primary, Baeck, M., additional, Marot, L., additional, Dumoutier, L., additional, and Buysschaert, M., additional
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- 2013
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12. Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22
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de Moura, P.R., primary, Watanabe, L., additional, Bleicher, L., additional, Colau, D., additional, Dumoutier, L., additional, Lemaire, M.M., additional, Renauld, J.-C., additional, and Polikarpov, I., additional
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- 2009
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13. Crystal structure of the IL-22/IL-22R1 complex
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Bleicher, L., primary, de Moura, P.R., additional, Watanabe, L., additional, Colau, D., additional, Dumoutier, L., additional, Renauld, J.-C., additional, and Polikarpov, I., additional
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- 2008
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14. Divergent roles of IFNs in the sensitization to endotoxin shock by lactate dehydrogenase-elevating virus
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Le-Thi-Phuong, T., primary, Dumoutier, L., additional, Renauld, J.-C., additional, Van Snick, J., additional, and Coutelier, J.-P., additional
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- 2007
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15. CRYSTAL STRUCTURE OF RECOMBINANT HUMAN INTERLEUKIN-22
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Nagem, R.A.P., primary, Colau, D., additional, Dumoutier, L., additional, Renauld, J.-C., additional, Ogata, C., additional, and Polikarpov, I., additional
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- 2003
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16. Crystallization and synchrotron X-ray diffraction studies of human interleukin-22
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Nagem, R. A. P., primary, Lucchesi, K. W., additional, Colau, D., additional, Dumoutier, L., additional, Renauld, J.-C., additional, and Polikarpov, I., additional
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- 2002
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17. IL-9 induces 24P3 lipocalin gene expression in murine T cell lymphomas
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Orabona, C., Dumoutier, L., and Jean-Christophe Renauld
18. IL-22 gene transfer in collagen-induced arthritis
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Apparailly, F, Dudler, J, Renauld, J-C, Plence, P, Dumoutier, L, Djouad, F, Noel, D, So, AK, Sany, J, and Jorgensen, C
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- 2004
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19. Régulation des réponses immunes humorales par la voie de signalisation IL-6 / STAT3
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Hercor, Mélanie, Andris, Fabienne, Vanhamme, Luc, Oberdan, Léo, Marini, Anna Maria, Flamand, Véronique, Bureau, Fabrice, Dumoutier, L, and Gueydan, Cyril
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STAT3 ,réponse humorale ,Immunologie ,lymphocytes Th2 ,Biologie moléculaire ,Biologie cellulaire ,lymphocytes Tfh - Abstract
L’aide fournie aux lymphocytes B par les lymphocytes T CD4+ est cruciale pour une réponse humorale de qualité. Les lymphocytes T helper folliculaires (Tfh) jouent un rôle majeur dans l’aide apportée aux lymphocytes B au sein des centres germinatifs et peu de choses sont connues sur la capacité d’aide des autres populations de cellules T CD4+. Le but de notre étude est d’évaluer la capacité d’aide aux lymphocytes B des lymphocytes T helper de type 2 (Th2), une population considérée, à l’origine, comme responsable de l’aide apportée aux lymphocytes B in vivo ainsi que d’analyser le rôle de l’axe IL6 / STAT3 dans la différenciation des lymphocytes Tfh et leur plasticité phénotypique. Nous montrons que les lymphocytes Th2 co-expriment des formes actives des facteurs de transcription STAT6 et STAT3 et que l’expression de STAT3 est requise pour la fonction d’aide aux lymphocytes B des lymphocytes Th2. Nous avons également pu montrer que la voie de signalisation IL-6 / STAT3 durant le développement des lymphocytes Tfh s’oppose à l’expression des gènes associés au programme de différenciation Th2., Option Biologie moléculaire du Doctorat en Sciences, info:eu-repo/semantics/nonPublished
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- 2015
20. Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma.
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Bick F, Brenis Gómez CM, Lammens I, Van Moorleghem J, De Wolf C, Dupont S, Dumoutier L, Smith NP, Villani AC, Browaeys R, Alladina J, Haring AM, Medoff BD, Cho JL, Bigirimana R, Vieira J, Hammad H, Blanchetot C, Schuijs MJ, and Lambrecht BN
- Abstract
Background: Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by T
H 2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes., Objective: IL-9 and IL-21 boost the activation and proliferation of TH 2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown., Methods: Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups., Results: IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH 2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets., Conclusion: IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH 2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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21. Keratinocytes activated by IL-4/IL-13 express IL-2Rγ with consequences on epidermal barrier function.
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Progneaux A, Evrard C, De Glas V, Fontaine A, Dotreppe C, De Vuyst E, Nikkels AF, García-González V, Dumoutier L, Lambert de Rouvroit C, and Poumay Y
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- Humans, Cells, Cultured, Epidermis metabolism, Interleukin-13 metabolism, Interleukin-4 metabolism, Janus Kinase Inhibitors, Keratinocytes metabolism, RNA, Messenger metabolism, Dermatitis, Atopic metabolism, Interleukin Receptor Common gamma Subunit metabolism
- Abstract
Atopic dermatitis (AD) is a Th2-type inflammatory disease characterized by an alteration of epidermal barrier following the release of IL-4 and IL-13. These cytokines activate type II IL-4Rα/IL-13Rα1 receptors in the keratinocyte. Whilst IL-2Rγ, that forms type I receptor for IL-4, is only expressed in haematopoietic cells, recent studies suggest its induction in keratinocytes, which questions about its role. We studied expression of IL-2Rγ in keratinocytes and its role in alteration of keratinocyte function and epidermal barrier. IL-2Rγ expression in keratinocytes was studied using both reconstructed human epidermis (RHE) exposed to IL-4/IL-13 and AD skin. IL-2Rγ induction by type II receptor has been analyzed using JAK inhibitors and RHE knockout (KO) for IL13RA1. IL-2Rγ function was investigated in RHE KO for IL2RG. In RHE, IL-4/IL-13 induce expression of IL-2Rγ at the mRNA and protein levels. Its mRNA expression is also visualized in keratinocytes of lesional AD skin. IL-2Rγ expression is low in RHE treated with JAK inhibitors and absent in RHE KO for IL13RA1. Exposure to IL-4/IL-13 alters epidermal barrier, but this alteration is absent in RHE KO for IL2RG. A more important induction of IL-13Rα2 is reported in RHE KO for IL2RG than in not edited RHE. These results demonstrate IL-2Rγ induction in keratinocytes through activation of type II receptor. IL-2Rγ is involved in the alteration of the epidermal barrier and in the regulation of IL-13Rα2 expression. Observation of IL-2Rγ expression by keratinocytes inside AD lesional skin suggests a role for this receptor subunit in the disease., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2023
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22. IL-17 and IL-22 are pivotal cytokines to delay wound healing of S. aureus and P. aeruginosa infected skin.
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Lecron JC, Charreau S, Jégou JF, Salhi N, Petit-Paris I, Guignouard E, Burucoa C, Favot-Laforge L, Bodet C, Barra A, Huguier V, Mcheik J, Dumoutier L, Garnier J, Bernard FX, Ryffel B, and Morel F
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- Mice, Humans, Animals, Interleukin-17 metabolism, Staphylococcus aureus metabolism, Tumor Necrosis Factor-alpha, Oncostatin M, Mice, Inbred C57BL, Interleukin-22, Pseudomonas aeruginosa metabolism, Methicillin-Resistant Staphylococcus aureus metabolism
- Abstract
Introduction: Although the presence of pathogens in skin wounds is known to delay the wound healing process, the mechanisms underlying this delay remain poorly understood. In the present study, we have investigated the regulatory role of proinflammatory cytokines on the healing kinetics of infected wounds., Methods: We have developed a mouse model of cutaneous wound healing, with or without wound inoculation with Staphylococcus aureus and Pseudomonas aeruginosa , two major pathogens involved in cutaneous wound bacterial infections., Results: Aseptic excision in C57BL/6 mouse skin induced early expression of IL-1β, TNFα and Oncostatin M (OSM), without detectable expression of IL-22 and IL-17A/F. S. aureus and P. aeruginosa wound inoculation not only increased the expression of IL-1β and OSM, but also induced a strong cutaneous expression of IL-22, IL-17A and IL-17F, along with an increased number of infiltrating IL-17A and/or IL-22-producing γδ T cells. The same cytokine expression pattern was observed in infected human skin wounds. When compared to uninfected wounds, mouse skin infection delayed the wound healing process. Injection of IL-1α, TNFα, OSM, IL-22 and IL-17 together in the wound edges induced delayed wound healing similar to that induced by the bacterial infection. Wound healing experiments in infected Rag2KO mice (deficient in lymphocytes) showed a wound healing kinetic similar to uninfected Rag2KO mice or WT mice. Rag2KO infected-skin lesions expressed lower levels of IL-17 and IL-22 than WT, suggesting that the expression of these cytokines is mainly dependent on γδ T cells in this model. Wound healing was not delayed in infected IL-17R/IL-22KO, comparable to uninfected control mice. Injection of recombinant IL-22 and IL-17 in infected wound edges of Rag2KO mice re-establish the delayed kinetic of wound healing, as in infected WT mice., Conclusion: These results demonstrate the synergistic and specific effects of IL-22 and IL-17 induced by bacterial infection delay the wound healing process, regardless of the presence of bacteria per se . Therefore, these cytokines play an unexpected role in delayed skin wound healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lecron, Charreau, Jégou, Salhi, Petit-Paris, Guignouard, Burucoa, Favot-Laforge, Bodet, Barra, Huguier, Mcheik, Dumoutier, Garnier, Bernard, Ryffel and Morel.)
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- 2022
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23. Blocking GARP-mediated activation of TGF-β1 did not alter innate or adaptive immune responses to bacterial infection or protein immunization in mice.
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Gaignage M, Zhang X, Stockis J, Dedobbeleer O, Michiels C, Cochez P, Dumoutier L, Coulie PG, and Lucas S
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- Animals, Antibodies, Monoclonal metabolism, Immunity, Immunization, Mice, T-Lymphocytes, Regulatory, Adaptive Immunity, Bacterial Infections immunology, Bacterial Infections metabolism, Membrane Proteins metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
Transmembrane protein GARP binds latent TGF-β1 to form GARP:(latent)TGF-β1 complexes on the surface of several cell types including Tregs, B-cells, and platelets. Upon stimulation, these cells release active TGF-β1. Blocking TGF-β1 activation by Tregs with anti-GARP:TGF-β1 mAbs overcomes resistance to PD1/PD-L1 blockade and induces immune-mediated regressions of murine tumors, indicating that Treg-derived TGF-β1 inhibits anti-tumor immunity. TGF-β1 exerts a vast array of effects on immune responses. For example, it favors differentiation of T
H 17 cells and B-cell switch to IgA production, two important processes for mucosal immunity. Here, we sought to determine whether treatment with anti-GARP:TGF-β1 mAbs would perturb immune responses to intestinal bacterial infection. We observed no aggravation of intestinal disease, no systemic dissemination, and no alteration of innate or adaptative immune responses upon oral gavage of C. rodentium in highly susceptible Il22r-/- mice treated with anti-GARP:TGF-β1 mAbs. To examine the effects of GARP:TGF-β1 blockade on Ig production, we compared B cell- and TH cell- responses to OVA or CTB protein immunization in mice carrying deletions of Garp in Tregs, B cells, or platelets. No alteration of adaptive immune responses to protein immunization was observed in the absence of GARP on any of these cells. Altogether, we show that antibody-mediated blockade of GARP:TGF-β1 or genetic deletion of Garp in Tregs, B cells or platelets, do not alter innate or adaptive immune responses to intestinal bacterial infection or protein immunization in mice. Anti-GARP:TGF-β1 mAbs, currently tested for cancer immunotherapy, may thus restore anti-tumor immunity without severely impairing other immune defenses. PRéCIS: Immunotherapy with GARP:TGF-β1 mAbs may restore anti-tumor immunity without impairing immune or inflammatory responses required to maintain homeostasis or host defense against infection, notably at mucosal barriers., (© 2021. The Author(s).)- Published
- 2022
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24. Chilblains observed during the COVID-19 pandemic cannot be distinguished from classic, cold-related chilblains
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De Greef A, Choteau M, Herman A, Bouzin C, Marot L, Dachelet C, Lelotte J, Hoton D, Dumoutier L, and Baeck M
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- Humans, Interferon Regulatory Factor-7, Interferon-alpha, Leukocytes, Mononuclear immunology, Myxovirus Resistance Proteins, Pandemics, RNA, Viral, SARS-CoV-2, COVID-19 complications, Chilblains diagnosis
- Abstract
Background: Type 1 interferon (IFN-I) response induced by SARS-CoV-2 has been hypothesized to explain the association between chilblain lesions (CL) and SARS-CoV-2 infection., Objective: To explore direct cytopathogenicity of SARS-CoV-2 in CL and to focus on IFN-I expression in patients with chilblains., Materials & Methods: A monocentric cohort of 43 patients presenting with CL from April 2020 to May 2021 were included. During this period, all CL were, a priori, considered to be SARS-CoV-2-related. RT-qPCR on nasopharyngeal swabs and measurements of anti-SARS-CoV-2 antibodies were performed. Anti-SARS-CoV-2 immunostainings as well as SARS-CoV-2 RT-qPCR were performed on biopsy specimens of CL and controls. Expression of MX1 and IRF7 was analysed on patients’ biopsy specimens and/or PBMC and compared with controls and/or chilblains observed before the pandemic. Serum IFN-α was also measured., Results: RT-qPCR was negative in all patients and serological tests were positive in 11 patients. Immunostaining targeting viral proteins confirmed the lack of specificity. SARS-CoV-2 RNA remained undetected in all CL specimens. MX1 immunostaining was positive in CL and in pre-pandemic chilblains compared to controls. MX1 and IRF7 expression was significantly increased in CL specimens but not in PBMC. Serum IFN-α was undetected in CL patients., Conclusion: CL observed during the pandemic do not appear to be directly related to SARS-CoV-2 infection, either based on viral cytopathogenicity or high IFN-I response induced by the virus.
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- 2022
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25. JAK/STAT: Why choose a classical or an alternative pathway when you can have both?
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Puigdevall L, Michiels C, Stewardson C, and Dumoutier L
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- Phosphorylation, Receptors, Cytokine genetics, Receptors, Cytokine metabolism, Signal Transduction physiology, Janus Kinases genetics, Janus Kinases metabolism, STAT Transcription Factors genetics, STAT Transcription Factors metabolism
- Abstract
A subset of cytokines triggers the JAK-STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these cytokines are dimers/trimers of transmembrane proteins devoid of intracellular kinase activity. Instead, they rely on Janus kinases (JAKs) for signal transduction. Classical JAK-STAT signalling involves phosphorylation of cytokine receptors' intracellular tyrosines, which subsequently serve as docking sites for the recruitment and activation of STATs. However, there is evidence to show that several cytokine receptors also use a noncanonical, receptor tyrosine-independent path to induce activation of STAT proteins. We identified two main alternative modes of STAT activation. The first involves an association between a tyrosine-free region of the cytokine receptor and STATs, while the second seems to depend on a direct interaction between JAK and STAT proteins. We were able to identify the use of noncanonical mechanisms by almost a dozen cytokine receptors, suggesting they have some importance. These alternative pathways and the receptors that employ them are discussed in this review., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
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- 2022
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26. Development of SARS-CoV2 humoral response including neutralizing antibodies is not sufficient to protect patients against fatal infection.
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Choteau M, Scohy A, Messe S, Luyckx M, Dechamps M, Montiel V, Yombi JC, Gruson D, Limaye N, Michiels T, and Dumoutier L
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- Adult, Aged, COVID-19 mortality, Female, Humans, Male, Middle Aged, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 immunology, Immunity, Humoral, SARS-CoV-2 immunology
- Abstract
More than a year after the start of the pandemic, COVID-19 remains a global health emergency. Although the immune response against SARS-CoV-2 has been extensively studied, some points remain controversial. One is the role of antibodies in viral clearance and modulation of disease severity. While passive transfer of neutralizing antibodies protects against SARS-CoV-2 infection in animal models, titers of anti-SARS-CoV-2 antibodies have been reported to be higher in patients suffering from more severe forms of the disease. A second key question for pandemic management and vaccine design is the persistence of the humoral response. Here, we characterized the antibody response in 187 COVID-19 patients, ranging from asymptomatic individuals to patients who died from COVID-19, and including patients who recovered. We developed in-house ELISAs to measure titers of IgG, IgM and IgA directed against the RBD or N regions in patient serum or plasma, and a spike-pseudotyped neutralization assay to analyse seroneutralization. Higher titers of virus-specific antibodies were detected in patients with severe COVID-19, including deceased patients, compared to asymptomatic patients. This demonstrates that fatal infection is not associated with defective humoral response. Finally, most of recovered patients still had anti-SARS-CoV-2 IgG more than 3 months after infection., (© 2022. The Author(s).)
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- 2022
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27. Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study.
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Dechamps M, De Poortere J, Martin M, Gatto L, Daumerie A, Bouzin C, Octave M, Ginion A, Robaux V, Pirotton L, Bodart J, Gerard L, Montiel V, Campion A, Gruson D, Van Dievoet MA, Douxfils J, Haguet H, Morimont L, Derive M, Jolly L, Bertrand L, Dumoutier L, Castanares-Zapatero D, Laterre PF, Horman S, and Beauloye C
- Abstract
Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1β and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients., Competing Interests: JD is the CEO and founder of QUALIblood s.a., a Belgian Contract Research Organization. LM and HH were employed by the company QUALIblood s.a. and authors MDer and LJ were employed by the company Inotrem s.a. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Foundation Saint-Luc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2022 Dechamps, De Poortere, Martin, Gatto, Daumerie, Bouzin, Octave, Ginion, Robaux, Pirotton, Bodart, Gerard, Montiel, Campion, Gruson, Van Dievoet, Douxfils, Haguet, Morimont, Derive, Jolly, Bertrand, Dumoutier, Castanares-Zapatero, Laterre, Horman and Beauloye.)
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- 2022
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28. A Targetable, Noncanonical Signal Transducer and Activator of Transcription 3 Activation Induced by the Y-Less Region of IL-22 Receptor Orchestrates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.
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Michiels C, Puigdevall L, Cochez P, Achouri Y, Cheou P, Hendrickx E, Dauguet N, Blanchetot C, and Dumoutier L
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- Animals, Citrobacter rodentium, Enterobacteriaceae Infections immunology, Interleukins pharmacology, Mice, Mice, Inbred C57BL, Interleukin-22, Imiquimod toxicity, Psoriasis chemically induced, Receptors, Interleukin physiology, STAT3 Transcription Factor physiology
- Abstract
Exacerbated IL-22 activity induces tissue inflammation and immune disorders such as psoriasis. However, because IL-22 is also essential for tissue repair and defense at barrier interfaces, targeting IL-22 activity to treat psoriasis bears the risk of deleterious effects at mucosal sites such as the gut. We previously showed in vitro that IL-22 signaling relies on IL-22 receptor alpha (IL-22Rα) Y-dependent and -independent pathways. The second depends on the C-terminal Y-less region of IL-22Rα and leads to a massive signal transducer and activator of transcription 3 (STAT3) activation. Because STAT3 activation is associated with the development of psoriasis, we hypothesized that the specific inhibition of the noncanonical STAT3 activation by the Y-less region of IL-22Rα could reduce psoriasis-like disease while leaving intact its tissue defense functions in the gut. We show that mice expressing a C-terminally truncated version of IL-22Rα (ΔCter
mut/mut mice) are protected from the development of psoriasis-like dermatitis lesions induced by imiquimod to a lesser extent than Il22ra-/- mice. In contrast, only Il22ra-/- mice lose weight after Citrobacter rodentium infection. Altogether, our data suggest that specific targeting of the noncanonical STAT3 activation by IL-22 could serve to treat psoriasis-like skin inflammation without affecting IL-22‒dependent tissue repair or barrier defense at other sites., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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29. Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22.
- Author
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Schnepf D, Hernandez P, Mahlakõiv T, Crotta S, Sullender ME, Peterson ST, Ohnemus A, Michiels C, Gentle I, Dumoutier L, Reis CA, Diefenbach A, Wack A, Baldridge MT, and Staeheli P
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Disease Susceptibility, Female, Gastrointestinal Microbiome drug effects, Gene Expression Profiling, Interleukins physiology, Intestinal Mucosa metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Real-Time Polymerase Chain Reaction, Rotavirus physiology, Interleukin-22, Anti-Bacterial Agents adverse effects, Interleukins metabolism, Rotavirus Infections etiology
- Abstract
The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1-/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2-/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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30. New insight in understanding the contribution of SGLT1 in cardiac glucose uptake: evidence for a truncated form in mice and humans.
- Author
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Ferté L, Marino A, Battault S, Bultot L, Van Steenbergen A, Bol A, Cumps J, Ginion A, Koepsell H, Dumoutier L, Hue L, Horman S, Bertrand L, and Beauloye C
- Subjects
- Animals, Biological Transport, Cells, Cultured, Glucose Transporter Type 4 antagonists & inhibitors, Glucose Transporter Type 4 metabolism, Hypoglycemic Agents pharmacology, Insulin pharmacology, Male, Mice, Inbred C57BL, Mice, Knockout, Phlorhizin pharmacology, Protein Isoforms, Rats, Wistar, Sodium-Glucose Transporter 1 antagonists & inhibitors, Sodium-Glucose Transporter 1 genetics, Mice, Rats, Glucose metabolism, Myocytes, Cardiac metabolism, Sodium-Glucose Transporter 1 metabolism
- Abstract
Although sodium glucose cotransporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidence using phlorizin, the most common inhibitor of SGLTs, has suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knockout mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1-knockout (
Δex1 KO) and control littermate (WT) mice either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT andΔex1 KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT orΔex1 KO-derived cardiomyocytes. However, higher concentrations (1 mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation independently from cardiomyocyte genotype. Interestingly, we discovered that mouse and human hearts expressed a shorter slc5a1 transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of slc5a1 transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart. NEW & NOTEWORTHY Ever since the discovery of its expression in the heart, SGLT1 has been considered as similar as the intestine and a potential contributor to cardiac glucose transport. For the first time, we have demonstrated that a slc5a1 transcript variant is present in the heart that has no significant impact on cardiac glucose handling.- Published
- 2021
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31. Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice.
- Author
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Low JT, Christie M, Ernst M, Dumoutier L, Preaudet A, Ni Y, Griffin MDW, Mielke LA, Strasser A, Putoczki TL, and O'Reilly LA
- Subjects
- Animals, Carcinogenesis, Gastritis etiology, Gastritis metabolism, Interleukin-11 metabolism, Interleukin-6 metabolism, Mice, Signal Transduction, Stomach Neoplasms metabolism, Gastritis pathology, NF-kappa B p50 Subunit metabolism, STAT1 Transcription Factor metabolism, Stomach Neoplasms etiology, Stomach Neoplasms pathology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Background & Aims: Activity of nuclear factor κB transcription factors and signaling via signal transducer and activator of transcription (STAT) are frequently altered in gastric cancer cells. Mice lacking NFKB1 (Nfkb1
-/- mice) develop invasive gastric cancer, and their gastric tissues have increased levels of cytokines, such as interleukin (IL) 6, IL22, IL11, and tumor necrosis factor (TNF), as well as increased activation of STAT1. We investigated whether these cytokines were required for STAT1 activation in gastric tissues of mice and critical for gastric tumorigenesis., Methods: We crossed Nfkb1-/- mice with Il6-/- , Il22-/- , Il11Rα-/- , and Tnf-/- mice. Stomach tissues from compound mutant mice were analyzed by histology, immunoblotting, and RNA sequencing. Lymphoid, myeloid, and epithelial cells were isolated from stomachs, and the levels of cytokines were determined by flow cytometric analysis., Results: Nfkb1-/- mice developed gastritis, oxyntic atrophy, gastric dysplasia, and invasive tumors, whereas Nfkb1-/- Stat1-/- mice did not, even when followed for as long as 2 years. The levels of Il6, Il11, Il22, and Tnf messenger RNA were increased in the body and antrum of the stomachs from Nfkb1-/- mice, from 3-6 months of age. However, Nfkb1-/- Il6-/- , Nfkb1-/- Il22-/- , and Nfkb1-/- Il11Rα-/- mice still developed gastric tumors, although the absence of IL11 receptor (IL11R) significantly reduced development of invasive gastric tumors. Stomachs from Nfkb1-/- Tnf-/- mice exhibited significantly less gastritis and oxyntic atrophy and fewer tumors than Nfkb1-/- mice. This correlated with reduced activation of STAT1 and STAT3 and fewer numbers of T cells and B cells infiltrating the gastric body. Loss of STAT1 or TNF significantly reduced expression of PD-L1 on epithelial and myeloid (CD11b+ ) cells in the gastric mucosa of Nfkb1-/- mice-indeed, to the levels observed on the corresponding cells from wild-type mice., Conclusions: In studies of gastric tumor development in knockout mice, we found that loss of NFKB1 causes increased expression of TNF in the stomach and thereby drives activation of STAT1, resulting in an inflammatory immune response and the development of gastric cancer. IL11R appears to be required for the progression of gastric tumors to the invasive stage. These findings suggest that inhibitors of TNF, and possibly also inhibitors of IL11/IL11Rα, might be useful in the treatment of gastric cancer., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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32. Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.
- Author
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La Sala G, Michiels C, Kükenshöner T, Brandstoetter T, Maurer B, Koide A, Lau K, Pojer F, Koide S, Sexl V, Dumoutier L, and Hantschel O
- Subjects
- A549 Cells, Antibodies genetics, Blotting, Western, Calorimetry, Crystallography, X-Ray, Flow Cytometry, Fluorescence Polarization, Fluorescent Antibody Technique, Humans, Mass Spectrometry, Protein Binding, Protein Domains immunology, STAT3 Transcription Factor genetics, STAT3 Transcription Factor immunology, Signal Transduction genetics, Signal Transduction physiology, Synthetic Biology, Antibodies metabolism, STAT3 Transcription Factor metabolism
- Abstract
The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms.
- Published
- 2020
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33. IL-9 exerts biological function on antigen-experienced murine T cells and exacerbates colitis induced by adoptive transfer.
- Author
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de Heusch M, Steenwinckel V, Cochez PM, Louahed J, Warnier G, Lemaire MM, Renauld JC, and Dumoutier L
- Subjects
- Animals, Colitis etiology, Colitis genetics, Colitis pathology, Disease Models, Animal, Hyaluronan Receptors genetics, Hyaluronan Receptors immunology, Interleukin-2 genetics, Interleukin-2 immunology, Interleukin-9 genetics, Mice, Mice, Knockout, Mice, SCID, Receptors, Interleukin-9 genetics, Receptors, Interleukin-9 immunology, Th17 Cells pathology, Th17 Cells transplantation, Th2 Cells pathology, Th2 Cells transplantation, Adoptive Transfer adverse effects, Colitis immunology, Interleukin-9 immunology, Th17 Cells immunology, Th2 Cells immunology
- Abstract
IL-9 is involved in various T cell-dependent inflammatory models including colitis, encepahlitis, and asthma. However, the regulation and specificity of IL-9 responsiveness by T cells during immune responses remains poorly understood. Here, we addressed this question using two different models: experimental colitis induced by transfer of naive CD4
+ CD45RBhigh T cells into immunodeficient mice, and OVA-specific T cell activation. In the colitis model, constitutive IL-9 expression exacerbated inflammation upon transfer of CD4+ CD45RBhigh T cells from WT but not from Il9r-/- mice, indicating that IL-9 acts directly on T cells. Suprisingly, such naïve CD4+ CD45RBhigh T cells failed to express the Il9r or respond to IL-9 in vitro, in contrast with CD4+ CD45RBlow T cells. By using OVA-specific T cells, we observed that T cells acquired the capacity to respond to IL-9 along with CD44 upregulation, after long-lasting (5 to 12 days) in vivo antigenic stimulation. Il9r expression was associated with Th2 and Th17 phenotypes. Interestingly, in contrast to the IL-2 response, antigen restimulation downregulated IL-9 responsiveness. Taken together, our results demonstrate that IL-9 does not act on naïve T cells but that IL-9 responsiveness is acquired by CD4+ T cells after in vivo activation and acquisition of memory markers such as CD44., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2020
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34. Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer.
- Author
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Salazar Y, Zheng X, Brunn D, Raifer H, Picard F, Zhang Y, Winter H, Guenther S, Weigert A, Weigmann B, Dumoutier L, Renauld JC, Waisman A, Schmall A, Tufman A, Fink L, Brüne B, Bopp T, Grimminger F, Seeger W, Pullamsetti SS, Huber M, and Savai R
- Subjects
- A549 Cells, Animals, Humans, Interleukin-17 immunology, Interleukin-9 immunology, Lung Neoplasms pathology, Mice, Neoplasm Metastasis, Th17 Cells pathology, Cell Movement immunology, Epithelial-Mesenchymal Transition immunology, Lung Neoplasms immunology, Th17 Cells immunology, Tumor Microenvironment immunology
- Abstract
Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on lung cancer biology by studying in vitro cocultures, in vivo mouse models, and human lung cancer tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17 cells was detected in human lung cancer tissue and correlated with poor survival. Coculturing lung cancer cells with Th9/Th17 cells or exposing them to the respective CM induced EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL-9 and IL-17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Coinjection of Th9/Th17 cells with tumor cells in WT, Rag1-/-, Il9r-/-, and Il17ra-/- mice altered tumor growth and metastasis. Accordingly, inhibition of IL-9 or IL-17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration and metastatic spreading and offering potentially novel therapeutic strategies.
- Published
- 2020
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35. Ozone-Induced Aryl Hydrocarbon Receptor Activation Controls Lung Inflammation via Interleukin-22 Modulation.
- Author
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Michaudel C, Bataille F, Maillet I, Fauconnier L, Colas C, Sokol H, Straube M, Couturier-Maillard A, Dumoutier L, van Snick J, Quesniaux VF, Togbe D, and Ryffel B
- Subjects
- Animals, Antibodies, Neutralizing immunology, Antibodies, Neutralizing therapeutic use, Basic Helix-Loop-Helix Transcription Factors genetics, CD4-Positive T-Lymphocytes immunology, Interleukin-17 immunology, Interleukin-17 metabolism, Interleukins genetics, Interleukins immunology, Lipoxins metabolism, Lung Injury drug therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, Pneumonia drug therapy, Receptors, Aryl Hydrocarbon genetics, Receptors, Interleukin-17 genetics, Respiratory Hypersensitivity drug therapy, Tryptophan metabolism, Interleukin-22, Basic Helix-Loop-Helix Transcription Factors metabolism, Interleukins metabolism, Lung Injury chemically induced, Lung Injury metabolism, Ozone adverse effects, Pneumonia chemically induced, Pneumonia metabolism, Receptors, Aryl Hydrocarbon metabolism, Respiratory Hypersensitivity chemically induced, Respiratory Hypersensitivity metabolism
- Abstract
Airborne ozone exposure causes severe lung injury and inflammation. The aryl hydrocarbon Receptor (AhR) (1), activated in pollutant-induced inflammation, is critical for cytokine production, especially IL-22 and IL-17A. The role of AhR in ozone-induced lung inflammation is unknown. We report here that chronic ozone exposure activates AhR with increased tryptophan and lipoxin A4 production in mice. AhR
-/- mice show increased lung inflammation, airway hyperresponsiveness, and tissue remodeling with an increased recruitment of IL-17A and IL-22-expressing cells in comparison to control mice. IL-17A- and IL-22-neutralizing antibodies attenuate lung inflammation in AhR-/- and control mice. Enhanced lung inflammation and recruitment of ILC3, ILC2, and T cells were observed after T cell-specific AhR depletion using the AhRCD4cre -deficient mice. Together, the data demonstrate that ozone exposure activates AhR, which controls lung inflammation, airway hyperresponsiveness, and tissue remodeling via the reduction of IL-22 expression., (Copyright © 2020 Michaudel, Bataille, Maillet, Fauconnier, Colas, Sokol, Straube, Couturier-Maillard, Dumoutier, van Snick, Quesniaux, Togbe and Ryffel.)- Published
- 2020
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36. IL-6 and IL-1β expression is increased in autologous serum skin test of patients with chronic spontaneous urticaria.
- Author
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de Montjoye L, Choteau M, Herman A, Hendrickx E, Chéou P, Baeck M, and Dumoutier L
- Subjects
- Female, Humans, Interleukin-1beta metabolism, Interleukin-6 metabolism, Leukocytes, Mononuclear metabolism, Male, RNA, Messenger, Chronic Urticaria diagnosis, Chronic Urticaria etiology, Gene Expression, Interleukin-1beta genetics, Interleukin-6 genetics, Skin Tests methods
- Published
- 2019
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37. Increased expression of IL-24 in chronic spontaneous urticaria.
- Author
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de Montjoye L, Herman A, Hendrickx E, Chéou P, Blanchetot C, Hofman E, Baeck M, and Dumoutier L
- Subjects
- Autoantibodies immunology, Chronic Urticaria metabolism, Humans, Immunoglobulin E immunology, Interleukins immunology, Interleukins metabolism, Mast Cells immunology, Mast Cells metabolism, RNA, Messenger metabolism, Chronic Urticaria diagnosis, Chronic Urticaria etiology, Gene Expression, Interleukins genetics
- Published
- 2019
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38. Endogenous IL-22 is dispensable for experimental glomerulonephritis.
- Author
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Gnirck AC, Wunderlich M, Becker M, Xiong T, Weinert E, Meyer-Schwesinger C, Dumoutier L, Renauld JC, Huber S, Panzer U, and Turner JE
- Subjects
- Animals, Female, Glomerulonephritis immunology, Glomerulonephritis pathology, Immunity, Cellular immunology, Immunity, Humoral immunology, Interferon-gamma biosynthesis, Interleukins genetics, Kidney pathology, Kidney Cortex metabolism, Kidney Glomerulus metabolism, Kidney Tubules metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Interleukin metabolism, T-Lymphocytes metabolism, Interleukin-22, Glomerulonephritis metabolism, Interleukins metabolism
- Abstract
In recent years, the cytokine interleukin (IL)-22 attracted considerable attention due to its important immunoregulatory function in barrier tissues, such as the gut, lung, and skin. Although a regenerative role of IL-22 in renal tubular damage has been demonstrated, the role of IL-22 in the immunopathogenesis of glomerular injury is still unknown. Here, we demonstrate that the IL-22 receptor is expressed in the glomerular compartment of the kidney and that IL-22 expression increases in the renal cortex after induction of glomerular injury in a mouse model for crescentic glomerulonephritis (cGN, nephrotoxic nephritis). We identified γδ T cells and T
H 17 cells as major sources for IL-22 in the nephritic kidney. However, neither genetic or antibody-mediated deletion of IL-22 nor genetic deficiency in its endogenous inhibitor IL-22Rα2 (IL-22 binding protein) resulted in substantial phenotypic differences in mice with cGN with respect to crescent formation, tubulointerstitial damage, and kidney function impairment. Similarly, we did not observe significant differences between wild-type or IL-22-deficient mice in a mouse model of secondary focal and segmental glomerulosclerosis (adriamycin-induced nephropathy). As shown previously, we detected concomitant upregulation of IL-17A and IFN-γ production by T cells during the course of cGN, providing alternative cytokine pathways that mediate glomerular injury in this model. In conclusion, we show here that endogenous IL-22 expression is redundant in different forms of glomerular injury, indicating that the IL-22-directed therapies that are being tested in various human diseases might not affect the kidney in patients with glomerular disease.- Published
- 2019
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39. IL-24 contributes to skin inflammation in Para-Phenylenediamine-induced contact hypersensitivity.
- Author
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Van Belle AB, Cochez PM, de Heusch M, Pointner L, Opsomer R, Raynaud P, Achouri Y, Hendrickx E, Cheou P, Warnier G, Renauld JC, Baeck M, and Dumoutier L
- Subjects
- Adult, Aged, Animals, Biopsy, Coloring Agents, Disease Models, Animal, Humans, Immunoglobulin E metabolism, Inflammation metabolism, Leukocyte Common Antigens metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Middle Aged, Phenylenediamines, Receptors, Interleukin metabolism, Skin metabolism, Interleukin-22, Cytokines metabolism, Dermatitis, Allergic Contact metabolism, Inflammation chemically induced, Interleukins metabolism, Skin drug effects
- Abstract
Para-Phenylenediamine (PPD) is an aromatic amine used in hair dyes and in temporary black henna tattoos, which is a frequent cause of allergic contact dermatitis (ACD). ACD is a skin inflammatory reaction characterized by modifications such as spongiosis, exocytosis and acanthosis. The aim of this study is to characterize the expression and the role of IL-20-related cytokines, including IL-19, IL-20, IL-22 and IL-24, in ACD. The expression of IL19, IL20, IL22 and IL24 is increased in affected skin from PPD allergic patients compared with uninvolved skin. In addition, the expression of these cytokines positively correlates with clinical symptoms. To assess their role in ACD, we set up a mouse model of PPD-induced allergic contact dermatitis and we showed that, in contrast to Il22-deficient mice, Il22ra1-, Il20rb- and Il24-deficient mice are partially protected against development of PPD-induced contact hypersensitivity. These mice have decreased ear thickening and less acanthosis compared with WT mice after PPD treatment. In addition, the absence of IL-22R, IL-20R2 or IL-24 affects the recruitment of neutrophils into the skin but not the total IgE production. Taken together, these results demonstrate the implication of IL-24 via the IL-20R type II receptor in the inflammatory process of ACD.
- Published
- 2019
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40. The TLR7 ligand R848 prevents mouse graft- versus -host disease and cooperates with anti-interleukin-27 antibody for maximal protection and regulatory T-cell upregulation.
- Author
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Gaignage M, Marillier RG, Cochez PM, Dumoutier L, Uyttenhove C, Coutelier JP, and Van Snick J
- Subjects
- Animals, Cytokines metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Immunomodulation drug effects, Ligands, Melanoma, Experimental, Mice, Neoplasm Transplantation, T-Lymphocytes, Regulatory immunology, Antibodies, Monoclonal pharmacology, Graft vs Host Disease prevention & control, Imidazoles pharmacology, Interleukin-27 antagonists & inhibitors, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory metabolism, Toll-Like Receptor 7 metabolism
- Abstract
In spite of considerable therapeutic progress, acute graft- versus -host disease still limits allogeneic hematopoietic cell transplantation. We recently reported that mouse infection with nidovirus lactate dehydrogenase elevating virus impairs disease in non-conditioned B6D2F1 recipients of parental B6 spleen cells. As this virus activates TLR7, we tested a pharmacological TLR7 ligand, R848, in this model and observed complete survival if donor and recipients were treated before transplantation. Mixed lymphocyte culture performed 48 h after R848-treatment of normal mice demonstrated that both T-cell allo-responsiveness and antigen presentation by CD11b
+ and CD8α+ dendritic cells were inhibited. These inhibitions were dependent on IFNAR-1 signaling. In the B6 to B6D2F1 transplantation model, R848 decelerated, but did not abrogate, donor T-cell implantation and activation. However, it decreased interferon-gamma, tumor necrosis factor-alpha and interleukin-27 while upregulating active transforming growth factor-beta 1 plasma levels. In addition, donor and recipient Foxp3+ regulatory T-cell numbers were increased in recipient mice and their elimination compromised disease prevention. R848 also strongly improved survival of lethally irradiated BALB/c recipients of B6 hematopoietic cells and this also correlated with an upregulation of CD4 and CD8 Foxp3+ regulatory T cells that could be further increased by inhibition of interleukin-27. The combination of anti-interleukin-27p28 mono -clonal antibody and R848 showed strong synergy in preventing disease in the B6 to B6D2F1 transplantation model when recipients were sublethally irradiated and this also correlated with upregulation of regulatory T cells. We conclude that R848 modulates multiple aspects of graft- versus -host disease and offers potential for safe allogeneic bone marrow transplantation that can be further optimized by inhibition of interleukin-27., (Copyright © 2019 Ferrata Storti Foundation.)- Published
- 2019
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41. Increased expression of interleukin-9 in patients with allergic contact dermatitis caused by p-phenylenediamine.
- Author
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Baeck M, Herman A, de Montjoye L, Hendrickx E, Chéou P, Cochez PM, and Dumoutier L
- Subjects
- Dermatitis, Allergic Contact genetics, Female, Gene Expression drug effects, Humans, Male, Phenylenediamines immunology, Dermatitis, Allergic Contact immunology, Gene Expression immunology, Interleukin-9 metabolism, Phenylenediamines adverse effects
- Abstract
Background: Allergic contact dermatitis has been described as a type IV reaction caused by antigen-specific T cells. Central roles for CD8
+ cytotoxic T cells as effector cells and CD4+ T cells as regulatory cells have been suggested. T helper (Th) 2 and Th1 cytokines have been implicated; however, the nature of the allergen influences the Th response., Objective: To determine the types of T cells and cytokines expressed in patients allergic to p-phenylenediamine (PPD)., Methods: Serial skin biopsies of areas with positive patch test reactions in 29 PPD-sensitized patients were collected. T cell markers and cytokine expression were analysed by flow cytometry and quantitative reverse transcription polymerase chain reaction in both skin and peripheral blood mononuclear cells (PBMCs) of sensitized patients., Results: We observed increased expression of T cell markers and Th2/Th9-associated cytokines in both skin and stimulated PBMCs of PPD-allergic patients. Moreover, interleukin (IL)-9 was mainly produced by Th9 cells, in both skin and PBMCs. Further investigations showed that Il9r-deficient mice were more affected in a PPD contact hypersensitivity model than wild-type mice., Conclusion: We did not confirm the preclinical presence of CD8+ T cells. However, the expression of different T cell markers positively correlated with patch test reactions. IL-9 expression was strongly upregulated and directly related to patch test severity. In addition, we showed that IL-9 has an anti-inflammatory role in a mouse model of PPD contact hypersensitivity., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2018
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42. Omalizumab in chronic spontaneous urticaria: A real-life experience of dose and intervals adjustments in Belgium.
- Author
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de Montjoye L, Herman A, Dumoutier L, Lambert M, Tromme I, and Baeck M
- Subjects
- Belgium, Chronic Disease, Dose-Response Relationship, Drug, Humans, Treatment Outcome, Anti-Allergic Agents administration & dosage, Omalizumab administration & dosage, Urticaria drug therapy
- Published
- 2018
- Full Text
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43. Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model.
- Author
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Broquet A, Jacqueline C, Davieau M, Besbes A, Roquilly A, Martin J, Caillon J, Dumoutier L, Renauld JC, Heslan M, Josien R, and Asehnoune K
- Subjects
- Animals, Disease Models, Animal, Mice, Interleukin-22, Interleukins analysis, Lung pathology, Neutrophil Infiltration, Pneumonia, Bacterial pathology, Pseudomonas Infections pathology, Receptors, Interleukin analysis
- Abstract
Pseudomonas aeruginosa is a major threat for immune-compromised patients. Bacterial pneumonia can induce uncontrolled and massive neutrophil recruitment ultimately leading to acute respiratory distress syndrome and epithelium damage. Interleukin-22 plays a central role in the protection of the epithelium. In this study, we aimed to evaluate the role of interleukin-22 and its soluble receptor IL-22BP in an acute Pseudomonas aeruginosa pneumonia model in mice. In this model, we noted a transient increase of IL-22 during Pseudomonas aeruginosa challenge. Using an antibody-based approach, we demonstrated that IL-22 neutralisation led to increased susceptibility to infection and to lung damage correlated with an increase in neutrophil accumulation in the lungs. On the contrary, rIL-22 administration or IL-22BP neutralisation led to a decrease in mouse susceptibility and lung damage associated with a decrease in neutrophil accumulation. This study demonstrated that the IL-22/IL-22BP system plays a major role during Pseudomonas aeruginosa pneumonia by moderating neutrophil accumulation in the lungs that ultimately leads to epithelium protection.
- Published
- 2017
- Full Text
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44. Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation.
- Author
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Martin JC, Wolk K, Bériou G, Abidi A, Witte-Händel E, Louvet C, Kokolakis G, Drujont L, Dumoutier L, Renauld JC, Sabat R, and Josien R
- Subjects
- Adult, Aged, Aminoquinolines, Animals, Antibodies, Blocking administration & dosage, Cells, Cultured, Female, Gene Knockout Techniques, Humans, Imiquimod, Keratinocytes pathology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Psoriasis chemically induced, Rats, Rats, Sprague-Dawley, Receptors, Interleukin genetics, Receptors, Interleukin immunology, Signal Transduction, Young Adult, Interleukin-22, Inflammation immunology, Interleukins metabolism, Keratinocytes metabolism, Psoriasis immunology, Receptors, Interleukin metabolism, Skin immunology
- Abstract
Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency ( Il22ra2
-/- ) displayed exacerbated disease that associated with enhanced expression of IL-22-inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti-IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis., (Copyright © 2017 by The American Association of Immunologists, Inc.)- Published
- 2017
- Full Text
- View/download PDF
45. Ccr6 Is Dispensable for the Development of Skin Lesions Induced by Imiquimod despite its Effect on Epidermal Homing of IL-22-Producing Cells.
- Author
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Cochez PM, Michiels C, Hendrickx E, Dauguet N, Warnier G, Renauld JC, and Dumoutier L
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Epidermis drug effects, Epidermis immunology, Epidermis pathology, Gene Knock-In Techniques, Homeodomain Proteins genetics, Imiquimod, Mice, Mice, Inbred C57BL, Mice, Knockout, Psoriasis immunology, Psoriasis pathology, T-Lymphocyte Subsets immunology, beta-Galactosidase genetics, Interleukin-22, Aminoquinolines toxicity, Interleukins immunology, Psoriasis chemically induced, Receptors, CCR6 genetics
- Abstract
Expression of the chemokine receptor Ccr6 is shared by most IL-22-producing cells, and Ccr6-deficient mice showed decreased IL-22 production and skin inflammation upon IL-23 intradermal injections. To determine whether this observation might be extended to another psoriasis model, we applied imiquimod on Ccr6-deficient mice. Although epidermal IL-22 production was decreased because of a deficient recruitment of γδ T cells in these mice, they were not protected against psoriatic lesions. When primary epidermis or dermis tissue culture cells from nontreated mice were stimulated ex vivo with IL-1α/IL-2/IL-23, we observed that Ccr6 is crucial for Il22 expression from epidermal but not dermal cultures. Taking advantage of Ccr6-LacZ-knock-in mice, we showed that Ccr6 is necessary for the homing of Ccr6-positive cells, probably a γδ T-cell subset, which represents the main potential IL-22 source in the epidermis. Similar results were observed in Rag1
-/- epidermis and dermis primary cultures, in which a subset of innate lymphoid cells expressing Ccr6 represents the main potential source of IL-22. Taken together, our data show that Ccr6 is not required for the development of skin lesions induced by imiquimod despite its effect on epidermal homing of IL-22-producing cells., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
46. Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosis Infection Does Not Require Interleukin-22.
- Author
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Porte R, Van Maele L, Muñoz-Wolf N, Foligné B, Dumoutier L, Tabareau J, Cayet D, Gosset P, Jonckheere N, Van Seuningen I, Chabalgoity JA, Simonet M, Lamkanfi M, Renauld JC, Sirard JC, and Carnoy C
- Subjects
- Animals, Disease Models, Animal, Female, Flagellin administration & dosage, Interleukins genetics, Intestinal Mucosa microbiology, Lipopolysaccharides immunology, Mice, Mice, Knockout, Recombinant Fusion Proteins, Signal Transduction, Toll-Like Receptors metabolism, Yersinia pseudotuberculosis Infections microbiology, Yersinia pseudotuberculosis Infections mortality, Interleukin-22, Flagellin immunology, Interleukins metabolism, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Yersinia pseudotuberculosis immunology, Yersinia pseudotuberculosis Infections immunology, Yersinia pseudotuberculosis Infections metabolism
- Abstract
Signaling through Toll-like receptors (TLRs), the main receptors in innate immunity, is essential for the defense of mucosal surfaces. It was previously shown that systemic TLR5 stimulation by bacterial flagellin induces an immediate, transient interleukin-22 (IL-22)-dependent antimicrobial response to bacterial or viral infections of the mucosa. This process was dependent on the activation of type 3 innate lymphoid cells (ILCs). The objective of the present study was to analyze the effects of flagellin treatment in a murine model of oral infection with Yersinia pseudotuberculosis (an invasive, Gram-negative, enteropathogenic bacterium that targets the small intestine). We found that systemic administration of flagellin significantly increased the survival rate after intestinal infection (but not systemic infection) by Y. pseudotuberculosis This protection was associated with a low bacterial count in the gut and the spleen. In contrast, no protection was afforded by administration of the TLR4 agonist lipopolysaccharide, suggesting the presence of a flagellin-specific effect. Lastly, we found that TLR5- and MyD88-mediated signaling was required for the protective effects of flagellin, whereas neither lymphoid cells nor IL-22 was involved., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
- Full Text
- View/download PDF
47. AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model.
- Author
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Cochez PM, Michiels C, Hendrickx E, Van Belle AB, Lemaire MM, Dauguet N, Warnier G, de Heusch M, Togbe D, Ryffel B, Coulie PG, Renauld JC, and Dumoutier L
- Subjects
- Animals, Cell Proliferation, Chemotaxis genetics, Disease Models, Animal, Imiquimod, Immunity, Innate genetics, Immunity, Innate immunology, Interleukins genetics, Mice, Mice, Knockout, Psoriasis pathology, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta metabolism, Receptors, Antigen, T-Cell, gamma-delta genetics, Receptors, Antigen, T-Cell, gamma-delta metabolism, Receptors, Aryl Hydrocarbon deficiency, Receptors, Aryl Hydrocarbon genetics, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Th17 Cells immunology, Th17 Cells metabolism, Interleukin-22, Aminoquinolines adverse effects, Chemotaxis immunology, Interleukins biosynthesis, Psoriasis etiology, Psoriasis metabolism, Receptors, Aryl Hydrocarbon metabolism
- Abstract
IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRβ(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRβ(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRβ(+) T cells and ILCs., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
48. Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection.
- Author
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Hernández PP, Mahlakoiv T, Yang I, Schwierzeck V, Nguyen N, Guendel F, Gronke K, Ryffel B, Hoelscher C, Dumoutier L, Renauld JC, Suerbaum S, Staeheli P, and Diefenbach A
- Subjects
- Animals, Caco-2 Cells, Cell Line, Chlorocebus aethiops, Cytokines genetics, Cytokines pharmacology, Dogs, Drug Synergism, Epithelial Cells immunology, Epithelial Cells metabolism, Epithelial Cells virology, Gene Expression drug effects, HT29 Cells, Humans, Immunoblotting, Interleukins genetics, Interleukins pharmacology, Intestinal Mucosa metabolism, Intestines immunology, Intestines virology, Madin Darby Canine Kidney Cells, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Receptors, Cytokine genetics, Receptors, Cytokine immunology, Reverse Transcriptase Polymerase Chain Reaction, Rotavirus Infections genetics, Rotavirus Infections virology, STAT1 Transcription Factor genetics, STAT1 Transcription Factor immunology, STAT1 Transcription Factor metabolism, Vero Cells, Interleukin-22, Cytokines immunology, Gene Expression immunology, Interleukins immunology, Rotavirus Infections immunology
- Abstract
The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.
- Published
- 2015
- Full Text
- View/download PDF
49. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo.
- Author
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Cuende J, Liénart S, Dedobbeleer O, van der Woning B, De Boeck G, Stockis J, Huygens C, Colau D, Somja J, Delvenne P, Hannon M, Baron F, Dumoutier L, Renauld JC, De Haard H, Saunders M, Coulie PG, and Lucas S
- Subjects
- Animals, Autoimmunity, Epitopes chemistry, Graft vs Host Disease, Humans, Membrane Proteins metabolism, Methylation, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Protein Binding, Protein Conformation, Transforming Growth Factor beta1 metabolism, Antibodies, Monoclonal chemistry, Immunosuppressive Agents chemistry, Membrane Proteins chemistry, T-Lymphocytes, Regulatory immunology, Transforming Growth Factor beta1 chemistry
- Abstract
Regulatory T cells (Tregs) are essential to prevent autoimmunity, but excessive Treg function contributes to cancer progression by inhibiting antitumor immune responses. Tregs exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-β1 (TGF-β1). On the Treg cell surface, TGF-β1 is in an inactive form bound to membrane protein GARP and then activated by an unknown mechanism. We demonstrate that GARP is involved in this activation mechanism. Two anti-GARP monoclonal antibodies were generated that block the production of active TGF-β1 by human Tregs. These antibodies recognize a conformational epitope that requires amino acids GARP137-139 within GARP/TGF-β1 complexes. A variety of antibodies recognizing other GARP epitopes did not block active TGF-β1 production by Tregs. In a model of xenogeneic graft-versus-host disease in NSG mice, the blocking antibodies inhibited the immunosuppressive activity of human Tregs. These antibodies may serve as therapeutic tools to boost immune responses to infection or cancer via a mechanism of action distinct from that of currently available immunomodulatory antibodies. Used alone or in combination with tumor vaccines or antibodies targeting the CTLA4 or PD1/PD-L1 pathways, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
- Full Text
- View/download PDF
50. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status.
- Author
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Everard A, Geurts L, Caesar R, Van Hul M, Matamoros S, Duparc T, Denis RG, Cochez P, Pierard F, Castel J, Bindels LB, Plovier H, Robine S, Muccioli GG, Renauld JC, Dumoutier L, Delzenne NM, Luquet S, Bäckhed F, and Cani PD
- Subjects
- Animals, Energy Metabolism, Female, Gene Deletion, Glucose metabolism, Humans, Intestines cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Nutritional Status, Obesity genetics, Obesity prevention & control, Epithelial Cells metabolism, Intestinal Mucosa metabolism, Myeloid Differentiation Factor 88 metabolism, Obesity metabolism
- Abstract
Obesity is associated with a cluster of metabolic disorders, low-grade inflammation and altered gut microbiota. Whether host metabolism is controlled by intestinal innate immune system and the gut microbiota is unknown. Here we report that inducible intestinal epithelial cell-specific deletion of MyD88 partially protects against diet-induced obesity, diabetes and inflammation. This is associated with increased energy expenditure, an improved glucose homeostasis, reduced hepatic steatosis, fat mass and inflammation. Protection is transferred following gut microbiota transplantation to germ-free recipients. We also demonstrate that intestinal epithelial MyD88 deletion increases anti-inflammatory endocannabinoids, restores antimicrobial peptides production and increases intestinal regulatory T cells during diet-induced obesity. Targeting MyD88 after the onset of obesity reduces fat mass and inflammation. Our work thus identifies intestinal epithelial MyD88 as a sensor changing host metabolism according to the nutritional status and we show that targeting intestinal epithelial MyD88 constitutes a putative therapeutic target for obesity and related disorders.
- Published
- 2014
- Full Text
- View/download PDF
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