106 results on '"Laurent Yvan-Charvet"'
Search Results
2. Fructooligosaccharides benefits on glucose homeostasis upon high-fat diet feeding require type 2 conventional dendritic cells
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Adélaïde Gélineau, Geneviève Marcelin, Melissa Ouhachi, Sébastien Dussaud, Lise Voland, Raoul Manuel, Ines Baba, Christine Rouault, Laurent Yvan-Charvet, Karine Clément, Roxane Tussiwand, Thierry Huby, and Emmanuel L. Gautier
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Science - Abstract
Abstract Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity. Here, we observed that short-term HFD induced dysbiosis, glucose intolerance and decreased intestinal RORγt+ CD4 T cells, including peripherally-induced Tregs and IL17-producing (Th17) T cells. However, supplementation of HFD-fed male mice with the fermentable dietary fiber fructooligosaccharides (FOS) was sufficient to maintain RORγt+ CD4 T cell subsets and microbial species known to induce them, alongside having a beneficial impact on glucose tolerance. FOS-mediated normalization of Th17 cells and amelioration of glucose handling required the cDC2 dendritic cell subset in HFD-fed animals, while IL-17 neutralization limited FOS impact on glucose tolerance. Overall, we uncover a pivotal role of cDC2 in the control of the immune and metabolic effects of FOS in the context of HFD feeding.
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- 2024
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3. Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death
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Marina Blanc, Lama Habbouche, Peng Xiao, Cynthia Lebeaupin, Marion Janona, Nathalie Vaillant, Marie Irondelle, Jérôme Gilleron, Florent Murcy, Déborah Rousseau, Carmelo Luci, Thibault Barouillet, Sandrine Marchetti, Sandra Lacas-Gervais, Laurent Yvan-Charvet, Philippe Gual, Alessandra K. Cardozo, and Béatrice Bailly-Maitre
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Cytology ,QH573-671 - Abstract
Abstract The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to β-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving β-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production. BI-1-deficient mice experience a decline in endocrine pancreatic function in physiological and pathophysiological conditions, namely obesity induced by high-fat diet (HFD). We observed early-onset diabetes characterized by hyperglycemia, reduced serum insulin levels, β-cell loss, increased pancreatic lipases and pro-inflammatory cytokines, and the progression of metabolic dysfunction. Pancreatic section analysis revealed that BI-1 deletion overburdens unfolded proinsulin in the ER of β-cells, confirmed by ultrastructural signs of ER stress with overwhelmed IRE1α endoribonuclease (RNase) activity in freshly isolated islets. ER stress led to β-cell dysfunction and islet loss, due to an increase in immature proinsulin granules and defects in insulin crystallization with the presence of Rod-like granules. These results correlated with the induction of autophagy, ER phagy, and crinophagy quality control mechanisms, likely to alleviate the atypical accumulation of misfolded proinsulin in the ER. In fine, BI-1 in β-cells limited IRE1α RNase activity from triggering programmed β-cell death through apoptosis and pyroptosis (caspase-1, IL-1β) via NLRP3 inflammasome activation and metabolic dysfunction. Pharmaceutical IRE1α inhibition with STF-083010 reversed β-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic β-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on β-cell function and insulin secretion. In pancreatic β-cells, BI-1 –/– deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, β-cell programmed cell death, and diabetes.
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- 2024
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4. LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition
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Sarah Proteau, Imène Krossa, Chrystel Husser, Maxime Guéguinou, Federica Sella, Karine Bille, Marie Irondelle, Mélanie Dalmasso, Thibault Barouillet, Yann Cheli, Céline Pisibon, Nicole Arrighi, Sacha Nahon‐Estève, Arnaud Martel, Lauris Gastaud, Sandra Lassalle, Olivier Mignen, Patrick Brest, Nathalie M Mazure, Frédéric Bost, Stéphanie Baillif, Solange Landreville, Simon Turcotte, Dan Hasson, Saul Carcamo, Christophe Vandier, Emily Bernstein, Laurent Yvan‐Charvet, Mitchell P Levesque, Robert Ballotti, Corine Bertolotto, and Thomas Strub
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calcium ,LKB1 ,SIK2 ,SLC8A1 ,uveal melanoma ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.
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- 2023
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5. T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
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Venetia Bazioti, Anouk M. La Rose, Sjors Maassen, Frans Bianchi, Rinse de Boer, Benedek Halmos, Deepti Dabral, Emma Guilbaud, Arthur Flohr-Svendsen, Anouk G. Groenen, Alejandro Marmolejo-Garza, Mirjam H. Koster, Niels J. Kloosterhuis, Rick Havinga, Alle T. Pranger, Miriam Langelaar-Makkinje, Alain de Bruin, Bart van de Sluis, Alison B. Kohan, Laurent Yvan-Charvet, Geert van den Bogaart, and Marit Westerterp
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Science - Abstract
Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr −/− mice.
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- 2022
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6. Brown adipose tissue monocytes support tissue expansion
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Alexandre Gallerand, Marion I. Stunault, Johanna Merlin, Hannah P. Luehmann, Deborah H. Sultan, Maria M. Firulyova, Virginie Magnone, Narges Khedher, Antoine Jalil, Bastien Dolfi, Alexia Castiglione, Adelie Dumont, Marion Ayrault, Nathalie Vaillant, Jérôme Gilleron, Pascal Barbry, David Dombrowicz, Matthias Mack, David Masson, Thomas Bertero, Burkhard Becher, Jesse W. Williams, Konstantin Zaitsev, Yongjian Liu, Rodolphe R. Guinamard, Laurent Yvan-Charvet, and Stoyan Ivanov
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Science - Abstract
Adipose tissue is composed of a number of adipocytes and a number of other cells including immune cells. Here the authors use single-cell sequencing of murine brown adipose tissue immune cells and describe multiple macrophage and monocyte subsets and show that monocytes contribute to brown adipose tissue expansion.
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- 2021
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7. Unravelling the sex-specific diversity and functions of adrenal gland macrophages
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Bastien Dolfi, Alexandre Gallerand, Maria M. Firulyova, Yingzheng Xu, Johanna Merlin, Adélie Dumont, Alexia Castiglione, Nathalie Vaillant, Sandrine Quemener, Heidi Gerke, Marion I. Stunault, Patricia R. Schrank, Seung-Hyeon Kim, Alisha Zhu, Jie Ding, Jerome Gilleron, Virginie Magnone, Pascal Barbry, David Dombrowicz, Christophe Duranton, Abdelilah Wakkach, Claudine Blin-Wakkach, Burkhard Becher, Sophie Pagnotta, Rafael J. Argüello, Pia Rantakari, Svetoslav Chakarov, Florent Ginhoux, Konstantin Zaitsev, Ki-Wook Kim, Laurent Yvan-Charvet, Rodolphe R. Guinamard, Jesse W. Williams, and Stoyan Ivanov
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CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We define the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and use genetic models to explore the developmental mechanisms yielding macrophage diversity. We define populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identify a female-specific subset with low major histocompatibility complex (MHC) class II expression. In adulthood, monocyte recruitment dominates adrenal gland macrophage maintenance in female mice. Adrenal gland macrophage sub-tissular distribution follows a sex-dimorphic pattern, with MHC class IIlow macrophages located at the cortico-medullary junction. Macrophage sex dimorphism depends on the presence of the cortical X-zone. Adrenal gland macrophage depletion results in altered tissue homeostasis, modulated lipid metabolism, and decreased local aldosterone production during stress exposure. Overall, these data reveal the heterogeneity of adrenal gland macrophages and point toward sex-restricted distribution and functions of these cells.
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- 2022
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8. Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
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Maria I. Matias, Carmen S. Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R. Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C. Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S. Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V. Swinnen, Stefan A. Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, and Valérie Dardalhon
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T cell differentiation ,Treg ,α-ketoglutarate ,lipidome ,triacylglyceride synthesis ,CAR T cells ,Biology (General) ,QH301-705.5 - Abstract
Summary: Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.
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- 2021
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9. ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms
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Manon Viaud, Omar Abdel-Wahab, Julie Gall, Stoyan Ivanov, Rodolphe Guinamard, Sophie Sore, Johanna Merlin, Marion Ayrault, Emma Guilbaud, Arnaud Jacquel, Patrick Auberger, Nan Wang, Ross L. Levine, Alan R. Tall, and Laurent Yvan-Charvet
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Biology (General) ,QH301-705.5 - Abstract
Summary: Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis. : Viaud et al. show that ABCA1 mutants identified in CMML patients diminish the tumor-suppressor functions of ABCA1 and cooperate with Tet2 loss to confer the hypersensitivity of myeloid progenitors to IL-3 receptor β canonical signaling, which can be prevented by raising HDL levels. Keywords: somatic mutations, leukemia biology, ATP-binding cassette transporter, cholesterol efflux, hematopoietic stem and progenitor cells, ten-eleven translocation 2
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- 2020
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10. Immunometabolism of Phagocytes and Relationships to Cardiac Repair
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Shuang Zhang, Gael Bories, Connor Lantz, Russel Emmons, Amanda Becker, Esther Liu, Michael M. Abecassis, Laurent Yvan-Charvet, and Edward B. Thorp
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macrophage ,neutrophil ,phagocyte ,immunometabolism ,hypoxia ,reperfusion ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.
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- 2019
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11. Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance
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Jérôme Gilleron, Gwennaëlle Bouget, Stoyan Ivanov, Cindy Meziat, Franck Ceppo, Bastien Vergoni, Mansour Djedaini, Antoine Soprani, Karine Dumas, Arnaud Jacquel, Laurent Yvan-Charvet, Nicolas Venteclef, Jean-François Tanti, and Mireille Cormont
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Biology (General) ,QH301-705.5 - Abstract
Summary: Obesity modifies T cell populations in adipose tissue, thereby contributing to adipose tissue inflammation and insulin resistance. Here, we show that Rab4b, a small GTPase governing endocytic trafficking, is pivotal in T cells for the development of these pathological events. Rab4b expression is decreased in adipose T cells from mice and patients with obesity. The specific depletion of Rab4b in T cells causes adipocyte hypertrophy and insulin resistance in chow-fed mice and worsens insulin resistance in obese mice. This phenotype is driven by an increase in adipose Th17 and a decrease in adipose Treg due to a cell-autonomous skew of differentiation toward Th17. The Th17/Treg imbalance initiates adipose tissue inflammation and reduces adipogenesis, leading to lipid deposition in liver and muscles. Therefore, we propose that the obesity-induced loss of Rab4b in adipose T cells may contribute to maladaptive white adipose tissue remodeling and insulin resistance by altering adipose T cell fate. : Gilleron et al. show that Rab4b expression is decreased in adipose T cells during obesity in mice and humans. They reveal that Rab4b in T cells is critical for the control of adipose tissue remodeling and insulin sensitivity by regulating the adipose Th17/Treg balance. Keywords: immunometabolism, small GTPase, endocytosis, adipose tissue, ectopic lipids
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- 2018
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12. Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation
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Vincent Sarrazy, Sophie Sore, Manon Viaud, Guylène Rignol, Marit Westerterp, Franck Ceppo, Jean-Francois Tanti, Rodolphe Guinamard, Emmanuel L. Gautier, and Laurent Yvan-Charvet
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Biology (General) ,QH301-705.5 - Abstract
Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr−/− mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis.
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- 2015
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13. Macrophage Origin, Metabolic Reprogramming and IL-1 Signaling: Promises and Pitfalls in Lung Cancer
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Emma Guilbaud, Emmanuel L. Gautier, and Laurent Yvan-Charvet
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lung adenocarcinoma ,macrophage ,immunotherapy ,interleukin-1 and immunometabolism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Macrophages are tissue-resident cells that act as immune sentinels to maintain tissue integrity, preserve self-tolerance and protect against invading pathogens. Lung macrophages within the distal airways face around 8000–9000 L of air every day and for that reason are continuously exposed to a variety of inhaled particles, allergens or airborne microbes. Chronic exposure to irritant particles can prime macrophages to mediate a smoldering inflammatory response creating a mutagenic environment and favoring cancer initiation. Tumor-associated macrophages (TAMs) represent the majority of the tumor stroma and maintain intricate interactions with malignant cells within the tumor microenvironment (TME) largely influencing the outcome of cancer growth and metastasis. A number of macrophage-centered approaches have been investigated as potential cancer therapy and include strategies to limit their infiltration or exploit their antitumor effector functions. Recently, strategies aimed at targeting IL-1 signaling pathway using a blocking antibody have unexpectedly shown great promise on incident lung cancer. Here, we review the current understanding of the bridge between TAM metabolism, IL-1 signaling, and effector functions in lung adenocarcinoma and address the challenges to successfully incorporating these pathways into current anticancer regimens.
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- 2019
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14. The OncoAge Consortium: Linking Aging and Oncology from Bench to Bedside and Back Again
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Paul Hofman, Nicholas Ayache, Pascal Barbry, Michel Barlaud, Audrey Bel, Philippe Blancou, Frédéric Checler, Sylvie Chevillard, Gael Cristofari, Mathilde Demory, Vincent Esnault, Claire Falandry, Eric Gilson, Olivier Guérin, Nicolas Glaichenhaus, Joel Guigay, Marius Ilié, Bernard Mari, Charles-Hugo Marquette, Véronique Paquis-Flucklinger, Frédéric Prate, Pierre Saintigny, Barbara Seitz-Polsky, Taycir Skhiri, Ellen Van Obberghen-Schilling, Emmanuel Van Obberghen, and Laurent Yvan-Charvet
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aging ,cancer ,optimization ,research ,education ,elderly ,well-being ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
It is generally accepted that carcinogenesis and aging are two biological processes, which are known to be associated. Notably, the frequency of certain cancers (including lung cancer), increases significantly with the age of patients and there is now a wealth of data showing that multiple mechanisms leading to malignant transformation and to aging are interconnected, defining the so-called common biology of aging and cancer. OncoAge, a consortium launched in 2015, brings together the multidisciplinary expertise of leading public hospital services and academic laboratories to foster the transfer of scientific knowledge rapidly acquired in the fields of cancer biology and aging into innovative medical practice and silver economy development. This is achieved through the development of shared technical platforms (for research on genome stability, (epi)genetics, biobanking, immunology, metabolism, and artificial intelligence), clinical research projects, clinical trials, and education. OncoAge focuses mainly on two pilot pathologies, which benefit from the expertise of several members, namely lung and head and neck cancers. This review outlines the broad strategic directions and key advances of OncoAge and summarizes some of the issues faced by this consortium, as well as the short- and long-term perspectives.
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- 2019
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15. SR-BI inhibits ABCG1-stimulated net cholesterol efflux from cells to plasma HDL
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Laurent Yvan-Charvet, Tamara A. Pagler, Nan Wang, Takafumi Senokuchi, May Brundert, Hongna Li, Franz Rinninger, and Alan R. Tall
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high density lipoprotein ,ATP binding cassette transporter G1 ,scavenger receptor class B type I ,lecithin:cholesterol acyltransferase ,liver X receptor ,macrophage ,Biochemistry ,QD415-436 - Abstract
This study compares the roles of ABCG1 and scavenger receptor class B type I (SR-BI) singly or together in promoting net cellular cholesterol efflux to plasma HDL containing active LCAT. In transfected cells, SR-BI promoted free cholesterol efflux to HDL, but this was offset by an increased uptake of HDL cholesteryl ester (CE) into cells, resulting in no net efflux. Coexpression of SR-BI with ABCG1 inhibited the ABCG1-mediated net cholesterol efflux to HDL, apparently by promoting the reuptake of CE from medium. However, ABCG1-mediated cholesterol efflux was not altered in cholesterol-loaded, SR-BI-deficient (SR-BI−/−) macrophages. Briefly cultured macrophages collected from SR-BI−/− mice loaded with acetylated LDL in the peritoneal cavity did exhibit reduced efflux to HDL. However, this was attributable to reduced expression of ABCG1 and ABCA1, likely reflecting increased macrophage cholesterol efflux to apolipoprotein E-enriched HDL during loading in SR-BI−/− mice. In conclusion, cellular SR-BI does not promote net cholesterol efflux from cells to plasma HDL containing active LCAT as a result of the reuptake of HDL-CE into cells. Previous findings of increased atherosclerosis in mice transplanted with SR-BI−/− bone marrow probably cannot be explained by a defect in macrophage cholesterol efflux.
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- 2008
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16. Inflamed macrophages sans mitochondrial pyruvate carrier?
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Laurent Yvan-Charvet and Edward Benjamin Thorp
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Physiology (medical) ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Cell Biology - Published
- 2023
17. Le métabolisme protège-t-il notre système immunitaire ?
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Laurent Yvan-Charvet and Béatrice Bailly-Maitre
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
18. Macrophage ontogeny and functional diversity in cardiometabolic diseases
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Emmanuel L. Gautier, Laurent Yvan-Charvet, Haoussa Askia, and Florent Murcy
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0303 health sciences ,Cell type ,Macrophages ,Ontogeny ,Adipose tissue ,Cell Differentiation ,Cell Biology ,030204 cardiovascular system & hematology ,Biology ,Embryonic stem cell ,Mice ,03 medical and health sciences ,Functional diversity ,0302 clinical medicine ,Immune system ,Cardiovascular Diseases ,Immunology ,Animals ,Humans ,Macrophage ,Homeostasis ,030304 developmental biology ,Developmental Biology - Abstract
Macrophages are the dominant immune cell types in the adipose tissue, the liver or the aortic wall and they were originally believed to mainly derived from monocytes to fuel tissue inflammation in cardiometabolic diseases. However, over the last decade the identification of tissue resident macrophages (trMacs) from embryonic origin in these metabolic tissues has provided a breakthrough in the field forcing to better comprehend macrophage diversity during pathological states. Infiltrated monocyte-derived macrophages (moMacs), similar to trMacs, adapt to the local metabolic environment that eventually shapes their functions. In this review, we will summarize the emerging versatility of macrophages in cardiometabolic diseases with a focus in the control of adipose tissue, liver and large vessels homeostasis.
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- 2021
19. LDL-cholesterol drives reversible myelomonocytic skewing in human bone marrow
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Laurent Yvan-Charvet, Marit Westerterp, Translational Immunology Groningen (TRIGR), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
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Ldl cholesterol ,0303 health sciences ,medicine.medical_specialty ,business.industry ,Human bone ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Medicine ,LDL Cholesterol Lipoproteins ,Cardiology and Cardiovascular Medicine ,business ,030304 developmental biology - Published
- 2021
20. T-cell Abca1 and Abcg1 cholesterol efflux pathways suppress T-cell apoptosis and senescence and increase atherosclerosis in middle-agedLdlr-/-mice
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Venetia Bazioti, Anouk M. La Rose, Sjors Maassen, Frans Bianchi, Rinse de Boer, Emma Guilbaud, Arthur Flohr-Svendsen, Anouk G. Groenen, Alejandro Marmolejo-Garza, Mirjam H. Koster, Niels J. Kloosterhuis, Alle T. Pranger, Miriam Langelaar-Makkinje, Alain de Bruin, Bart van de Sluis, Alison B. Kohan, Laurent Yvan-Charvet, Geert van den Bogaart, and Marit Westerterp
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lipids (amino acids, peptides, and proteins) - Abstract
Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T-cells accumulate cholesterol, which could lead to a pro-inflammatory phenotype. However, the role of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) in T-cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generated mice with T-cell-specificAbca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T-cellAbca1/Abcg1-deficiency decreased blood, lymph node, and splenic T-cells, and increased T-cell activation and apoptosis. T-cellAbca1/Abcg1-deficiency induced a premature T-cell aging phenotype in middle-aged (12-13 months)Ldlr-/-mice, reflected by upregulation of senescence markers. Despite T-cell senescence and enhanced T-cell activation, T-cellAbca1/Abcg1-deficiency decreased atherosclerosis and aortic inflammation in middle-agedLdlr-/-mice, accompanied by decreased T-cells in atherosclerotic plaques. We attribute these effects to T-cell apoptosis downstream of T-cell activation. Collectively, T-cell cholesterol efflux pathways are critical for maintaining T-cell numbers, suppress senescence, and induce atherosclerosis in middle-agedLdlr-/-mice.
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- 2022
21. Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity
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Géraldine Gonfrier, Laurent Yvan-Charvet, Laurent Bailly, Julie Contenti, Christelle Pomares-Estran, David Chirio, Laurent Boyer, Céline Loubatier, Orane Visvikis, Michel Carles, Océane Dufies, Patrick Munro, Arnaud Jacquel, Cedric Torre, Sébastien Vitale, Anne Doye, Valérie Giordanengo, Johan Courjon, Stoyan Ivanov, Jean Dellamonica, Romain Lotte, Patrick Auberger, and Alexandre Robert
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0301 basic medicine ,Clinical Trials and Observations ,Inflammasomes ,Stimulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Humans ,Myeloid Cells ,Prospective Studies ,Prospective cohort study ,Innate immune system ,business.industry ,SARS-CoV-2 ,Case-control study ,COVID-19 ,Inflammasome ,Hematology ,Middle Aged ,Peripheral ,030104 developmental biology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Immunology ,Biomarker (medicine) ,business ,Biomarkers ,medicine.drug - Abstract
Key Points Measurement of NLRP3 inflammasome activation in the blood of patients reveals an impaired immature neutrophil response in severe COVID-19. Inflammasome signature analysis in circulating myeloid cells allows COVID-19 patients to be stratified and predicts evolution., Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient’s evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017., Visual Abstract
- Published
- 2021
22. REDD1 deficiency protects against nonalcoholic hepatic steatosis induced by high‐fat diet
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Karine Dumas, Pascal Peraldi, Faustine Pastor, Chaima Ayachi, Rodolphe Anty, Sandra Lacas-Gervais, Nathalie Vaillant, Stéphanie Patouraux, Philippe Gual, Albert Tran, Jean-François Tanti, Laurent Yvan-Charvet, Sophie Giorgetti-Peraldi, Mireille Cormont, François Bertrand Favier, Stéphanie Bonnafous, Jerome Gilleron, Université Côte d'Azur, Inserm, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 'Cellular and Molecular Pathophysiology of Obesity and Diabetes', Université Côte d'Azur, Centre Commun de Microscopie Appliquée (CCMA), Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), Université Côte d'Azur, Inserm, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 'Haematometabolism in Diseases', Université Côte d'Azur, Inserm, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 'Chronic Liver Diseases Associated with Steatosis', Fédération d'Hépatologie, Centre Hospitalier Universitaire de Nice (CHU Nice), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Tanti, Jean-François, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
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Adult ,Male ,0301 basic medicine ,autophagy ,obesity ,medicine.medical_specialty ,Diet, High-Fat ,Chronic liver disease ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,Mitophagy ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Beta oxidation ,Cells, Cultured ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,2. Zero hunger ,Carnitine O-Palmitoyltransferase ,business.industry ,hepatic steatosis ,Autophagy ,REDD1 ,Lipid metabolism ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,3. Good health ,Fatty Acid Synthase, Type I ,030104 developmental biology ,Endocrinology ,Female ,Steatosis ,Sterol Regulatory Element Binding Protein 1 ,business ,Gene Deletion ,Stearoyl-CoA Desaturase ,030217 neurology & neurosurgery ,Transcription Factors ,Biotechnology - Abstract
International audience; Nonalcoholic fatty liver disease is a chronic liver disease which is associated with obesity and insulin resistance. We investigated the implication of REDD1 (Regulated in development and DNA damage response-1), a stress-induced protein in the development of hepatic steatosis. REDD1 expression was increased in the liver of obese mice and morbidly obese patients, and its expression correlated with hepatic steatosis and insulin resistance in obese patients. REDD1 deficiency protected mice from the development of hepatic steatosis induced by high-fat diet (HFD) without affecting body weight gain and glucose intolerance. This protection was associated with a decrease in the expression of lipogenic genes, SREBP1c, FASN, and SCD-1 in liver of HFD-fed REDD1-KO mice. Healthy mitochondria are crucial for the adequate control of lipid metabolism and failure to remove damaged mitochondria is correlated with liver steatosis. Expression of markers of autophagy and mitophagy, Beclin, LC3-II, Parkin, BNIP3L, was enhanced in liver of HFD-fed REDD1-KO mice. The number of mitochondria showing colocalization between LAMP2 and AIF was increased in liver of HFD-fed REDD1-KO mice. Moreover, mitochondria in liver of REDD1-KO mice were smaller than in WT. These results are correlated with an increase in PGC-1α and CPT-1 expression, involved in fatty acid oxidation. In conclusion, loss of REDD1 protects mice from the development of hepatic steatosis.
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- 2020
23. Regulatory T cell differentiation is controlled by alpha KG-induced alterations in mitochondrial metabolism and lipid homeostasis
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Julie Perrault, Anais Rivière, Chloe Goldsmith, Jonas Dehairs, Cédric Mongellaz, Laurent Yvan-Charvet, Naomi Taylor, Valérie S. Zimmermann, Saverio Tardito, Maria I. Matias, Valerie Dardalhon, Océane Delos, Amir Foroushani, Kandice R. Levental, Stefan A. Muljo, Sandrina Kinet, Ilya Levental, Hector Hernandez-Vargas, Ali Talebi, Jean-Charles Portais, Justine Bertand-Michel, Madeline Wong, Ameeta Kelekar, Julien C. Marie, Johannes V. Swinnen, Carmen S M Yong, Erdinc Sezgin, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Peter Mac Callum Cancer Centre, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institute, University of Virginia, Leuven Cancer Institute [Leuven, Belgium] (LKI), MetaboHUB-MetaToul, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Minnesota [MN, USA], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Cancer Research UK Beatson Institute [Glasgow], National Cancer Institute [Bethesda] (NCI-NIH), and Dardalhon, Valérie
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mitochondrial metabolism ,Fibrosarcoma ,T cell differentiation ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Immunotherapy, Adoptive ,T-Lymphocytes, Regulatory ,GLUCOSE ,Th1 ,ACTIVATION ,Homeostasis ,Biology (General) ,Cells, Cultured ,Mice, Knockout ,CAR T cells ,Receptors, Chimeric Antigen ,DNA methylation ,Chemistry ,DIACYLGLYCEROL ACYLTRANSFERASE ,FOXP3 ,Cell Differentiation ,Forkhead Transcription Factors ,Lipidome ,Mitochondria ,Cell biology ,SUCCINATE-DEHYDROGENASE ,Treg ,Phenotype ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology ,Cytokines ,Ketoglutaric Acids ,Signal transduction ,Life Sciences & Biomedicine ,Intracellular ,Signal Transduction ,REDUCTIVE GLUTAMINE-METABOLISM ,EXPRESSION ,Regulatory T cell differentiation ,QH301-705.5 ,FATE ,INHIBITION ,Oxidative phosphorylation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,lipidome ,[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Animals ,Humans ,Diacylglycerol O-Acyltransferase ,TCA cycle ,MTORC1 ,Science & Technology ,Cell Biology ,Th1 Cells ,Lipid Metabolism ,Mice, Inbred C57BL ,Citric acid cycle ,KETOGLUTARATE ,α-ketoglutarate ,Energy Metabolism ,triacylglyceride synthesis - Abstract
Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate. ispartof: CELL REPORTS vol:37 issue:5 ispartof: location:United States status: published
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- 2021
24. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation
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Amanda Swain, Alexandre Gallerand, Judith C. Sluimer, François Orange, Erik A.L. Biessen, Alexia Castiglione, Inna Gaisler-Salomon, Stefania Carobbio, Laurent Yvan-Charvet, Rodolphe Guinamard, Thierry Berton, Julie Gall, Johanna Merlin, Stephen Rayport, Alexey Sergushichev, Jean-Charles Martin, Marion I. Stunault, Maxim N. Artyomov, Adélie Dumont, Edward B. Thorp, Marion Ayrault, Emmanuel L. Gautier, Justine Masson, Stoyan Ivanov, Pierre Maechler, Nathalie Vaillant, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), ITMO University [Russia], Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), The institute of cancer research [London], Université Côte d'Azur (UCA), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Genève = University of Geneva (UNIGE), The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] (CAM), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), The New York State Psychiatric Institute (NYSPI), Columbia University [New York], University of Haifa [Haifa], Washington University School of Medicine [Saint Louis, MO], Centre Commun de Microscopie Appliquée [Nice] (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Northwestern University [Chicago, Ill. USA], RWTH Aachen University, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Northwestern University Medical School [Chicago], Pathologie, RS: Carim - B07 The vulnerable plaque: makers and markers, and Gautier, Emmanuel
- Subjects
EXPRESSION ,PROMOTES ,Endocrinology, Diabetes and Metabolism ,Glutamine ,[SDV]Life Sciences [q-bio] ,Cellular detoxification ,Oxidative phosphorylation ,METABOLISM ,MOUSE ,Oxidative Phosphorylation ,Apoptotic cell clearance ,03 medical and health sciences ,Mice ,0302 clinical medicine ,MITOCHONDRIA ,Phagocytosis ,MESH: Oxidative Phosphorylation ,Physiology (medical) ,Internal Medicine ,Macrophage ,Animals ,MESH: Animals ,CELL ,Efferocytosis ,ddc:612 ,MESH: Phagocytosis ,ELECTRON-TRANSPORT ,MESH: Mice ,Tissue homeostasis ,030304 developmental biology ,Amination ,MESH: Amination ,0303 health sciences ,MESH: Glutamine ,Glutaminolysis ,Chemistry ,Cell Biology ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,030217 neurology & neurosurgery - Abstract
Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans. Merlin et al. find that non-canonical glutamine transamination is required for macrophage efferocytosis in atherosclerotic plaques by sustaining redox buffering and fueling energy production for cytoskeletal rearrangements.
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- 2021
25. A subset of Kupffer cells regulates metabolism through the expression of CD36
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Guochen Wan, Nicholas Ang, Shanshan W. Howland, Svetoslav Chakarov, Evan W. Newell, Gregoire Gessain, Wan Ting Kong, Cecilia Morgantini, Olivier N. F. Cexus, Bernett Lee, Zhaoyuan Liu, Xenia Ficht, Ping Chen, Giorgia De Simone, Emelie Barreby, Josephine Lum, Nicolas Venteclef, Francesco Andreata, Ahad Khalilnezhad, Myriam Aouadi, Jinmiao Chen, Connie Xu, Xiaomeng Zhang, Ivy Low, Foo Shihui, Garett Dunsmore, Anis Larbi, Laurent Yvan-Charvet, Camille Blériot, Wei Guo, Rhea Pai, Muhammad Faris Bin Mohd Kairi, Benoit Malleret, Radoslaw M. Sobota, Wint Wint Phoo, Florent Ginhoux, Lai Guan Ng, Valerio Azzimato, Marc Bajénoff, Raphaelle Ballaire, Matteo Iannacone, Valeria Fumagalli, Ankur Sharma, Akhila Balachander, Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Karolinska Institute, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Inovarion, IRCCS San Raffaele Scientific Institute [Milan, Italie], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Equipe Electronique - Laboratoire GREYC - UMR6072, Groupe de Recherche en Informatique, Image et Instrumentation de Caen (GREYC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], Shangaï Jiao Tong University [Shangaï], Genome Institute of Singapore (GIS), National University of Singapore (NUS), University of Surrey (UNIS), Agency for science, technology and research [Singapore] (A*STAR), Aix Marseille Université (AMU), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Immunité et métabolisme dans le diabète = IMmunity and MEtabolism in DIABetes [CRC] (IMMEDIAB Lab), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Shanghai Jiao Tong University [Shanghai], Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Inserm Avenir Group, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U1015, Unit of Immunology, Rheumatology, Allergy and Rare diseases, Milan (IRCCS San Raffaele Scientific Institute), E-institute of Shanghai University Immunology Division, Shanghai University, University of Surrey, - Biosciences and Medicine, Faculty of Health and Medical Sciences, Guildford, SingMass National Laboratory - Singapore, Bleriot, C., Barreby, E., Dunsmore, G., Ballaire, R., Chakarov, S., Ficht, X., De Simone, G., Andreata, F., Fumagalli, V., Guo, W., Wan, G., Gessain, G., Khalilnezhad, A., Zhang, X. M., Ang, N., Chen, P., Morgantini, C., Azzimato, V., Kong, W. T., Liu, Z., Pai, R., Lum, J., Shihui, F., Low, I., Xu, C., Malleret, B., Kairi, M. F. M., Balachander, A., Cexus, O., Larbi, A., Lee, B., Newell, E. W., Ng, L. G., Phoo, W. W., Sobota, R. M., Sharma, A., Howland, S. W., Chen, J., Bajenoff, M., Yvan-Charvet, L., Venteclef, N., Iannacone, M., Aouadi, M., Ginhoux, F., Bleriot, C, Barreby, E, Dunsmore, G, Ballaire, R, Chakarov, S, Ficht, X, De Simone, G, Andreata, F, Fumagalli, V, Guo, W, Wan, G, Gessain, G, Khalilnezhad, A, Zhang, X, Ang, N, Chen, P, Morgantini, C, Azzimato, V, Kong, W, Liu, Z, Pai, R, Lum, J, Shihui, F, Low, I, Xu, C, Malleret, B, Kairi, M, Balachander, A, Cexus, O, Larbi, A, Lee, B, Newell, E, Ng, L, Phoo, W, Sobota, R, Sharma, A, Howland, S, Chen, J, Bajenoff, M, Yvan-Charvet, L, Venteclef, N, Iannacone, M, Aouadi, M, Ginhoux, F, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
CD36 Antigens ,Kupffer Cells ,CD36 ,[SDV]Life Sciences [q-bio] ,Immunology ,Population ,Kupffer cell ,macrophage ,liver ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,scRNA-seq ,medicine ,Immunology and Allergy ,Gene silencing ,Macrophage ,Animals ,Obesity ,education ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,biology ,Fatty acid metabolism ,high fat diet ,medicine.disease ,Phenotype ,Cell biology ,macrophages ,single cell ,Oxidative Stress ,Infectious Diseases ,chemistry ,CD206 ,Liver ,030220 oncology & carcinogenesis ,biology.protein ,Steatosis ,heterogeneity ,metabolism - Abstract
Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM– population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.
- Published
- 2021
26. Mesothelial cell CSF1 sustains peritoneal macrophage proliferation
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Rodolphe Guinamard, Marilyn Gros, Nathalie Vaillant, Johanna Merlin, Marion I. Stunault, Stoyan Ivanov, Laurent Yvan-Charvet, Alexandre Gallerand, UMR_ S- 1065, C3M, and Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Macrophage colony-stimulating factor ,Stromal cell ,Cell Survival ,[SDV]Life Sciences [q-bio] ,Immunology ,Gene Expression ,Mice, Transgenic ,Cell Communication ,Biology ,Epithelium ,Mice ,03 medical and health sciences ,Peritoneal cavity ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Macrophage ,Efferocytosis ,Peritoneal Cavity ,ComputingMilieux_MISCELLANEOUS ,Tissue homeostasis ,030304 developmental biology ,0303 health sciences ,Macrophage Colony-Stimulating Factor ,Cell Membrane ,Epithelial Cells ,Coculture Techniques ,3. Good health ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Macrophages, Peritoneal ,Stromal Cells ,Extracellular Space ,Macrophage proliferation ,Mesothelial Cell ,Signal Transduction - Abstract
Macrophages play a central role during infection, inflammation and tissue homeostasis maintenance. Macrophages have been identified in all organs and their core transcriptomic signature and functions differ from one tissue to another. Interestingly, macrophages have also been identified in the peritoneal cavity and these cells have been extensively used as a model for phagocytosis, efferocytosis and polarization. Peritoneal macrophages are involved in B-cell IgA production, control of inflammation and wound healing following thermal-induced liver surface injury. These cells presumably require and interact with the omentum, where milky spot stromal cells have been proposed to secrete CSF1 (colony stimulating factor 1). Peritoneal macrophages depend on CSF1 for their generation and survival, but the identity of CSF1 producing cells inside the large peritoneal cavity remains unknown. Here we investigated peritoneal macrophage localization and their interaction with mesothelial cells, the major cell type predicted to secrete CSF1. Our data revealed that mesothelial cells produce membrane bound and secreted CSF1 that both sustain peritoneal macrophage growth.
- Published
- 2019
27. Cholesterol Mass Efflux Capacity, Incident Cardiovascular Disease, and Progression of Carotid Plaque
- Author
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Liana Tascau, Steven Shea, Robyn L. McClelland, Sandi Shrager, Alan R. Tall, Laurent Yvan-Charvet, Neal W. Jorgensen, Jay W. Heinecke, and James H. Stein
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0301 basic medicine ,medicine.medical_specialty ,Cholesterol ,business.industry ,Subgroup analysis ,Odds ratio ,030204 cardiovascular system & hematology ,Lower risk ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Internal medicine ,Diabetes mellitus ,Cohort ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Stroke ,Body mass index - Abstract
Objective— To assess the role of HDL (high-density lipoprotein)-mediated cholesterol mass efflux capacity (CMEC) in incident cardiovascular disease and carotid plaque progression. Approach and Results— We measured CMEC in 2 cohorts aged 45 to 84 years at baseline derived from the MESA (Multi-Ethnic Study of Atherosclerosis). Cohort 1 comprised 465 cases with incident cardiovascular disease events during 10 years of follow-up and 465 age- and sex-matched controls; cohort 2 comprised 407 cases with progression of carotid plaque measured by ultrasonography at 2 exams >10 years and 407 similarly matched controls. Covariates and outcome events were ascertained according to the MESA protocol. CMEC level was modestly correlated with HDL cholesterol ( R =0.13; P P =0.031] in the fully adjusted model) in cohort 1 but higher odds of carotid plaque progression (odds ratio, 1.24 per SD of CMEC [95% CI, 1.04–1.48; P =0.018] in the fully adjusted model) in cohort 2 but without dose-response effect. In subgroup analysis within cohort 1, higher CMEC was associated with lower risk of incident coronary heart disease events (odds ratio, 0.72 per SD of CMEC (95% CI, 0.5–0.91; P =0.007) while no association was found with stroke events. Conclusions— These findings support a role for HDL-mediated cholesterol efflux in an atheroprotective mechanism for coronary heart disease but not stroke.
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- 2019
28. Mitochondria orchestrate macrophage effector functions in atherosclerosis
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Thibault Barouillet, Andrew J. Murphy, Laurent Yvan-Charvet, ManKS. Lee, and Adélie Dumont
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0301 basic medicine ,Clinical Biochemistry ,Mitochondrion ,Biology ,Endoplasmic Reticulum ,Biochemistry ,Mice ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Mitophagy ,Animals ,Humans ,Macrophage ,Epigenetics ,Molecular Biology ,Macrophages ,Endoplasmic reticulum ,General Medicine ,Atherosclerosis ,Plaque, Atherosclerotic ,Mitochondria ,3. Good health ,Cell biology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Signal transduction ,Biogenesis - Abstract
Macrophages are pivotal in the initiation and development of atherosclerotic cardiovascular diseases. Recent studies have reinforced the importance of mitochondria in metabolic and signaling pathways to maintain macrophage effector functions. In this review, we discuss the past and emerging roles of macrophage mitochondria metabolic diversity in atherosclerosis and the potential avenue as biomarker. Beyond metabolic functions, mitochondria are also a signaling platform integrating epigenetic, redox, efferocytic and apoptotic regulations, which are exquisitely linked to their dynamics. Indeed, mitochondria functions depend on their density and shape perpetually controlled by mitochondria fusion/fission and biogenesis/mitophagy balances. Mitochondria can also communicate with other organelles such as the endoplasmic reticulum through mitochondria-associated membrane (MAM) or be secreted for paracrine actions. All these functions are perturbed in macrophages from mouse or human atherosclerotic plaques. A better understanding and integration of how these metabolic and signaling processes are integrated and dictate macrophage effector functions in atherosclerosis may ultimately help the development of novel therapeutic approaches.
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- 2021
- Full Text
- View/download PDF
29. Mitochondrial Metabolism Drives Triacylglycerol Synthesis to Control Regulatory T Cell Differentiation
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Madeline Wong, Ilya Levental, Kandice R. Levental, Anais Rivière, Ali Talebi, Erdinc Sezgin, Naomi Taylor, Laurent Yvan-Charvet, Johannes V. Swinnen, Saverio Tardito, Valérie S. Zimmermann, Valerie Dardalhon, Stefan A. Muljo, Jonas Dehair, Amir Foroushani, Carmen S M Yong, Cédric Mongellaz, Sandrina Kinet, Maria I. Matias, and Julie Perrault
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Regulatory T cell differentiation ,Adoptive cell transfer ,Regulatory T cell ,Chemistry ,FOXP3 ,hemic and immune systems ,chemical and pharmacologic phenomena ,Oxidative phosphorylation ,Cell biology ,Citric acid cycle ,medicine.anatomical_structure ,medicine ,Signal transduction ,Intracellular - Abstract
Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways. However, the impact of intracellular metabolites on Treg fate has not been well explored. Here we show that the α-ketoglutarate (αKG) tricarboxylic acid (TCA) cycle metabolite increases oxidative phosphorylation (OXPHOS) in naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating Foxp3+ Treg differentiation and increasing inflammatory cytokine expression. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration and decreased Foxp3 expression. Mechanistically, αKG-induced OXPHOS is associated with lipidome remodelling, characterized by augmented mitochondrial lipids and triacylglyceride (TAG) stores. Inhibiting succinate dehydrogenase, the bridging enzyme between the TCA cycle and the ETC, enforces Treg differentiation. Strikingly, TAG storage directly promotes an inflammatory phenotype –– Treg differentiation is restored by inhibiting DGAT2-mediated TAG synthesis. Thus, we identify a novel crosstalk between αKG, mitochondrial metabolism and DGAT2-mediated TAG synthesis in controlling Treg fate.
- Published
- 2021
30. Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy
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Emmanuel L. Gautier, Amélie Lacombe, Dominique Farabos, Christine Rouault, Camille Gamblin, Antonin Lamaziere, Laurent Yvan-Charvet, Francina Langa-Vives, Karine Clément, Isabelle Dugail, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Institut Pasteur [Paris]-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,MESH: 3T3 Cells ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Adipose tissue ,Endoplasmic Reticulum ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,MESH: Cholesterol ,Adipocyte ,Adipocytes ,MESH: Obesity ,MESH: Thermogenesis ,MESH: Animals ,MESH: Lipid Metabolism ,MESH: Sterol Esterase ,MESH: Middle Aged ,Chemistry ,Thermogenesis ,3T3 Cells ,Middle Aged ,[SDV] Life Sciences [q-bio] ,Cholesterol ,medicine.anatomical_structure ,Adult ,MESH: Triglycerides ,medicine.medical_specialty ,Lipolysis ,030209 endocrinology & metabolism ,03 medical and health sciences ,MESH: Endoplasmic Reticulum ,Lysosome ,Internal medicine ,Autophagy ,Internal Medicine ,medicine ,Animals ,Humans ,MESH: Autophagy ,MESH: Lipolysis ,Obesity ,MESH: Mice ,Triglycerides ,MESH: Adipocytes ,MESH: Humans ,MESH: Adult ,Sterol Esterase ,Lipid Metabolism ,Sterol regulatory element-binding protein ,030104 developmental biology ,Endocrinology ,Homeostasis - Abstract
International audience; Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes, is unclear. We show that the isolated adipocyte fraction, but not the total undigested adipose tissue (ATs), from obese patients has decreased LAL expression compared with that from nonobese people. Lentiviral-mediated LAL knockdown in the 3T3L1 mouse cell line to mimic the obese adipocytes condition did not affect lysosome density or autophagic flux, but it did increase triglyceride storage and disrupt endoplasmic reticulum cholesterol, as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than did control mice fed a high-fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol level in the former was lower than that of control mice, although triglyceridemia in the two groups of mice was similar. The adipose-specific LAL-overexpressing mouse phenotype depends on the housing temperature and develops only under mild hypothermic stress (e.g., room temperature) but not at thermoneutrality (30°C), demonstrating the prominent contribution of brown AT (BAT) thermogenesis. LAL overexpression increased levels of BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue-cholesterol homeostasis and affects BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.
- Published
- 2020
31. Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis
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Tan Siyun Lucinda, Charles-Antoine Dutertre, Mark B Y Tang, Satoshi Nakamizo, Josephine Lum, Laurent Yvan-Charvet, Shawn Lim, Feriel Hacini-Rachinel, Geraldine Koh, Florent Ginhoux, Emma Guttman-Yassky, Masashi Iwata, Tsuyoshi Goto, Charlene Foong, Pearly Yong, Kaori Tomari, Reiko Sato, Xiaomeng Zhang, Kenji Kabashima, Rintaro Shibuya, Ahad Khalilnezhad, Valérie Julia, Colin Theng, Kahbing Jasmine Tan, Benoit Malleret, Helen He, and Baptiste Janela
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0301 basic medicine ,CD14 ,T cell ,Immunology ,Population ,Interleukin-1beta ,Lipopolysaccharide Receptors ,Gene Expression ,Human skin ,Biology ,Dermatitis, Atopic ,03 medical and health sciences ,0302 clinical medicine ,Single-cell analysis ,Psoriasis ,medicine ,Immunology and Allergy ,Macrophage ,Humans ,Gene Regulatory Networks ,education ,Interleukin-15 ,education.field_of_study ,Macrophages ,Dendritic cell ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Langerhans Cells ,Interleukin-23 Subunit p19 ,Single-Cell Analysis - Abstract
Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.
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- 2020
32. Lysosomal acid lipase drives adipocyte cholesterol homeostasis and modulates lipid storage in obesity, independent of autophagy
- Author
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Isabelle Dugail, Laurent Yvan-Charvet, Emmanuel L. Gautier, Karine Clément, Antonin Lamaziere, Dominique Farabos, Francina Langa-Vives, Amélie Lacombe, Christine Rouault, Camille Gamblin, and Ada Admin
- Abstract
Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes is unclear. We show that the isolated adipocyte fraction but not the total undigested adipose tissue from obese patients has decreased LAL expression compared to non-obese. Lentiviral-mediated LAL knockdown in 3T3L1 to mimic obese adipocytes condition did not affect lysosome density or autophagic flux, but increased triglyceride storage and disrupted ER cholesterol as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than controls on a high fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol was lower than controls albeit similar triglyceridemia. Adipose-LAL overexpressing mice phenotype is dependent on the housing temperature, and develops only under mild hypothermic stress (room temperature) but not at thermoneutrality (30°C), demonstrating prominent contribution of BAT thermogenesis. LAL overexpression increased BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue cholesterol homeostasis and impacts BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.
- Published
- 2020
33. Non-canonical glutamine transamination metabolism sustains efferocytosis by coupling oxidative stress buffering to oxidative phosphorylation
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François Orange, Stoyan Ivanov, Stephen Rayport, Marion Ayrault, Alexey Sergushichev, Maxim N. Artyomov, Nathalie Vaillant, Inna Gaisler-Salomon, Erik A.L. Biessen, Adélie Dumont, Johanna Merlin, Rodolphe Guinamard, Pierre Maechler, Marion I. Stunault, Edward B. Thorp, Emmanuel L. Gautier, Alexandre Gallerand, Judith C. Sluimer, Justine Masson, Laurent Yvan-Charvet, Julie Gall, Stefania Carobbio, Thierry Berton, Jean-Charles Martin, and Amanda Swain
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chemistry.chemical_classification ,Glutamine ,Coupling (electronics) ,chemistry ,Non canonical ,Transamination ,Biophysics ,medicine ,Metabolism ,Oxidative phosphorylation ,Efferocytosis ,medicine.disease_cause ,Oxidative stress - Abstract
Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal glutaminase (Gls) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis. In addition, impaired macrophage glutaminolysis exacerbated atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlated with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling revealed that macrophage efferocytic capacity rely on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (Glud1) to fuel ɑ-ketogulatrate-dependent immunometabolism. This pathway was necessary to meet the unique requirements of efferocytosis for cellular detoxification and high energy cytoskeletal rearrangements. Thus, we uncovered a novel role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease.
- Published
- 2020
34. αKG inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism
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Valerie Dardalhon, Sandrina Kinet, Naomi Taylor, Madeline Wong, J. Dehair, Ilya Levental, Erdinc Sezgin, Maria I. Matias, Cédric Mongellaz, Stefan A. Muljo, Valérie S. Zimmermann, Carmen S M Yong, Triantafyllos Chavakis, Johan Swinnen, Laurent Yvan-Charvet, Kandice R. Levental, Amir Foroushani, Saverio Tardito, and Ali Talebi
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Citric acid cycle ,Regulatory T cell differentiation ,medicine.anatomical_structure ,Chemistry ,Regulatory T cell ,Effector ,medicine ,Glycolysis ,Oxidative phosphorylation ,Lipidome ,Mitochondrion ,Cell biology - Abstract
The differentiation of CD4 T cells to a specific effector fate is metabolically regulated, integrating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) with transcriptional and epigenetic changes. OXPHOS is tightly coordinated with the tricarboxylic acid (TCA) cycle but the precise role of TCA intermediates in CD4 T cell differentiation remain unclear. Here we demonstrate that α-ketoglutarate (αKG) inhibited regulatory T cell (Treg) generation while conversely, increasing Th1 polarization. In accord with these data, αKG promoted the effector profile of Treg-polarized chimeric antigen receptor-engineered T cells against the ErbB2 tumor antigen. Mechanistically, αKG significantly altered transcripts of genes involved in lipid-related processes, inducing a robust lipidome-wide remodelling and decreased membrane fluidity. A massive increase in storage and mitochondria lipids was associated with expression of mitochondrial genes and a significantly augmented OXPHOS. Notably, inhibition of succinate dehydrogenase activity, the bridge between the TCA cycle and the electron transport chain, enforced Treg generation. Thus, our study identifies novel connections between αKG, lipidome remodelling and OXPHOS in CD4 T cell fate decisions.
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- 2020
35. Liver X receptors are required for thymic resilience and T cell output
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Nina K. Harder, Jyoti Patel, Florian Kahles, Yoshiko Iwamoto, John E. Mindur, Cameron S. McAlpine, Jan-Åke Gustafsson, Ruslan I. Sadreyev, Laurent Yvan-Charvet, Filip K. Swirski, Shun He, Henrike Janssen, David R. Koolbergen, Wolfram C. Poller, Lai Ping Wong, Ashley M. Fenn, Christopher T. Chan, Sara Rattik, Alan R. Tall, Carlos Fernández-Hernando, Anja M. van der Laan, Marit Westerterp, Colin Valet, Atsushi Anzai, Matthias Nahrendorf, Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR), Cardiothoracic Surgery, Cardiology, Amsterdam Cardiovascular Sciences, and ACS - Heart failure & arrhythmias
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T cell ,Immunology ,Experimental autoimmune encephalomyelitis ,T lymphocyte ,Biology ,medicine.disease ,Acquired immune system ,Article ,Cell biology ,Negative selection ,Metabolism ,medicine.anatomical_structure ,medicine ,Immunodeficiency ,Immunology and Allergy ,Involution (medicine) ,Liver X receptor ,Transcription factor - Abstract
Liver X receptors (LXRs) orchestrate cholesterol metabolism with diverse metabolic and immune functions. Chan et al. show that in the thymus, thymic epithelial cells protect against involution and promote regeneration, whereas T cells require LXRs to escape negative selection., The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)—a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity—critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ’s functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ’s indispensable roles in adaptive immunity.
- Published
- 2020
36. Metabolic Inflammation in Obesity-At the Crossroads between Fatty Acid and Cholesterol Metabolism
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Julie Gall, Laurent Yvan-Charvet, Rachel Byrne, Sean Curley, and Fiona C. McGillicuddy
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0301 basic medicine ,Adipose tissue macrophages ,Adipose tissue ,Inflammation ,Bioinformatics ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Insulin resistance ,Non-alcoholic Fatty Liver Disease ,medicine ,Animals ,Humans ,Obesity ,chemistry.chemical_classification ,030109 nutrition & dietetics ,Cholesterol ,business.industry ,Fatty Acids ,Fatty acid ,medicine.disease ,3. Good health ,030104 developmental biology ,chemistry ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,medicine.symptom ,business ,Dyslipidemia ,Food Science ,Biotechnology - Abstract
Scope Metabolic inflammation is a classic hallmark of obesity that is associated with numerous cardiometabolic complications. Disturbances in fatty acid and cholesterol metabolism are evident in obesity and likely intricately linked to the development and/or sustainment of metabolic inflammation and insulin resistance. Elevations in triglyceride-rich lipoproteins and reductions in high-density lipoprotein-cholesterol in turn are two major disturbances that accompany obesity. Methods and results How metabolic dyslipidemia may contribute to metabolic inflammation is discussed. How aberrant cholesterol homeostasis coupled with excessive fatty acid accumulation prime pro-IL-1β and the evidence to support a synergistic partnership between cholesterol and fatty acids in driving metabolic inflammation are also discussed. Further, pharmaceutical and nutraceutical strategies aimed at attenuating low-grade inflammation and implications for cardiometabolic complications of obesity are reviewed. The current literature on the importance of the local tissue microenvironment in activating adipose tissue macrophages within obese adipose tissue and the contribution of these local immune cells to metabolic inflammation is reviewed. Finally, the limitations to current biomarkers of metabolic inflammation and the importance of novel sensitive biomarkers in driving obesity sub-type characterization to direct personalized medicine approaches to obesity treatment in the future are discussed.
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- 2020
37. Myeloid Cell Diversity and Impact of Metabolic Cues during Atherosclerosis
- Author
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Laurent Yvan-Charvet, Johanna Merlin, Marion I. Stunault, Rodolphe Guinamard, Alexandre Gallerand, Stoyan Ivanov, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0303 health sciences ,Myeloid ,business.industry ,[SDV]Life Sciences [q-bio] ,Cell ,Inflammation ,General Medicine ,Dendritic cell ,030204 cardiovascular system & hematology ,Bioinformatics ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,medicine ,Macrophage ,Myeloid cell homeostasis ,medicine.symptom ,business ,Intracellular ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology - Abstract
Myeloid cells are key contributors to tissue, immune and metabolic homeostasis and their alteration fuels inflammation and associated disorders such as atherosclerosis. Conversely, in a classical chicken-and-egg situation, systemic and local metabolism, together with receptor-mediated activation, regulate intracellular metabolism and reprogram myeloid cell functions. Those regulatory loops are notable during the development of atherosclerotic lesions. Therefore, understanding the intricate metabolic mechanisms regulating myeloid cell biology could lead to innovative approaches to prevent and treat cardiovascular diseases. In this review, we will attempt to summarize the different metabolic factors regulating myeloid cell homeostasis and contribution to atherosclerosis, the most frequent cardiovascular disease.
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- 2020
38. Le sommeil protège-t-il nos vaisseaux sanguins ?
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Laurent Yvan-Charvet, Johanna Merlin, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Programme ATIP - Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sciences, EDP, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
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business.industry ,[SDV]Life Sciences [q-bio] ,MEDLINE ,General Medicine ,030204 cardiovascular system & hematology ,Sleep in non-human animals ,General Biochemistry, Genetics and Molecular Biology ,[SDV] Life Sciences [q-bio] ,03 medical and health sciences ,0302 clinical medicine ,Anesthesia ,Medicine ,030212 general & internal medicine ,business ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2019
39. Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD
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Xu Shi, Robert E. Gerszten, Maria Hamm de Miguel, Olle Melander, Alan R. Tall, Joanne Hsieh, Renu Regunathan-Shenk, Yuan Zhang, Jonathan Hogan, Annie J. Febus, Eric Lai, Jessica R. Singer, Rafael Lantigua, Martin Magnusson, Nan Wang, Anjali Ganda, Andrew J. Murphy, Nora Bijl, Serge Cremers, Farah N. Hussain, Ying Wang, Linda Vernocchi, Rupali S. Avasare, Bibhas Chakraborty, Laurent Yvan-Charvet, and Kristie M. Gordon
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Male ,0301 basic medicine ,medicine.medical_specialty ,Disease ,030204 cardiovascular system & hematology ,Pharmacology ,Monocytes ,Article ,Cell Line ,Cytokine Receptor Common beta Subunit ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Carnitine ,Internal medicine ,medicine ,Humans ,Diabetic Nephropathies ,Renal Insufficiency, Chronic ,Molecular Biology ,Aged ,Kidney ,biology ,Cholesterol ,Biological Transport ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,ABCG1 ,chemistry ,Cardiovascular Diseases ,ABCA1 ,Metabolome ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Efflux ,Animal studies ,Cardiology and Cardiovascular Medicine ,ATP Binding Cassette Transporter 1 ,Follow-Up Studies ,Kidney disease - Abstract
Patients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implications for cardiovascular disease.We recruited 120 CKD patients (eGFR30mL/min/1.73mThere was a strong positive correlation between cell-surface IL-3Rβ levels and monocyte counts in CKD (P0.001). ABCA1 mRNA was reduced in CKD vs. control monocytes (P0.05), across various etiologies of CKD. Cholesterol efflux to apolipoprotein A1 was impaired in monocytes from CKD patients with diabetic nephropathy (P0.05), but we found no evidence for a circulating HDL-mediated defect in cholesterol efflux in CKD. Profiling of plasma metabolites showed that medium-chain acylcarnitines were both independently associated with lower levels of cholesterol transporter mRNA in CKD monocytes at baseline (P0.05), and with cardiovascular events in CKD patients after median 2.6years of follow-up.Cholesterol efflux in humans varies in terms of cellular components. We report a cellular defect in ABCA1-mediated cholesterol efflux in monocytes from CKD patients with diabetic nephropathy. Unlike several traditional risk factors for atherosclerotic cardiovascular disease, plasma metabolites inversely associated with endogenous cholesterol transporters predicted cardiovascular events in CKD patients. (Funded by the National Institute of Diabetes and Digestive and Kidney DiseasesK23DK097288 and others.).
- Published
- 2017
40. Can LDL cholesterol be too low? Possible risks of extremely low levels
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Paolo Parini, Angel Cedazo-Minguez, Laurent Yvan-Charvet, Matti J. Tikkanen, Gerd Assmann, Bo Angelin, Jonathan C. Cohen, Dirk Müller-Wieland, Ingemar Björkhem, Christoph J. Binder, J. Starup-Linde, Robert S. Rosenson, A. von Eckardstein, Anders G. Olsson, Eduardo Farinaro, Klaus G. Parhofer, University of Zurich, and Olsson, A G
- Subjects
MONOCLONAL-ANTIBODY ,Heart disease ,medicine.medical_treatment ,Disease ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Bioinformatics ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Neoplasms ,540 Chemistry ,030212 general & internal medicine ,10038 Institute of Clinical Chemistry ,biology ,abetalipoproteinaemia ,Brain ,HMG-COA REDUCTASE ,3. Good health ,Lipoproteins, LDL ,hypocholesterolaemia ,CARDIOVASCULAR-DISEASE ,Cardiovascular Diseases ,Low-density lipoprotein ,HMG-CoA reductase ,MENDELIAN RANDOMIZATION ,CORONARY-ARTERY-DISEASE ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,safety ,Hypercholesterolemia ,LOW-DENSITY-LIPOPROTEIN ,BRAIN CHOLESTEROL ,610 Medicine & health ,HEART-DISEASE ,Bone and Bones ,Immune System Phenomena ,03 medical and health sciences ,Internal Medicine ,medicine ,Humans ,HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA ,Adverse effect ,Cholesterol ,business.industry ,SUBTILISIN/KEXIN TYPE 9 ,Cholesterol, LDL ,medicine.disease ,Steroid hormone ,low-density lipoprotein ,Diabetes Mellitus, Type 2 ,chemistry ,2724 Internal Medicine ,Mutation ,Immunology ,adverse effects ,biology.protein ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business - Abstract
Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.This is an article from the symposium: Risks and benefits of Extremely Low LDL Cholesterol.
- Published
- 2017
41. HIF-2α in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis
- Author
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Stephen D. Miller, Matthew DeBerge, Holger K. Eltzschig, Edward B. Thorp, Shirley Dehn, Deyu Fang, Xin-Yi Yeap, and Laurent Yvan-Charvet
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Reactive oxygen species ,Cytokine Suppression ,Phagocytosis ,Immunology ,Inflammation ,Biology ,Cell biology ,Proinflammatory cytokine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,medicine ,Immunology and Allergy ,Macrophage ,Scavenger receptor ,medicine.symptom ,Ex vivo - Abstract
Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (MΦ) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2α during other key MΦ functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunoprecipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco. Concordantly, Hif-2α−/− MΦs exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting MΦs through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes MΦ quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.
- Published
- 2016
42. Granulopoiesis and Neutrophil Homeostasis: A Metabolic, Daily Balancing Act
- Author
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Lai Guan Ng, Laurent Yvan-Charvet, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)
- Subjects
0301 basic medicine ,Neutrophils ,[SDV]Life Sciences [q-bio] ,Immunology ,Inflammation ,Biology ,Granulopoiesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Animals ,Homeostasis ,Humans ,Progenitor cell ,Neutrophil homeostasis ,Myelopoiesis ,Macrophages ,Haematopoiesis ,030104 developmental biology ,Gene Expression Regulation ,Disease Susceptibility ,Stem cell ,medicine.symptom ,Energy Metabolism ,Biomarkers ,030215 immunology ,Granulocytes - Abstract
Granulopoiesis is part of the hematopoietic hierarchic architecture, where hematopoietic stem cells give rise to highly proliferative multipotent and lineage-committed granulocytic progenitor cells that differentiate into unipotent neutrophil progenitors. Given their short lifespan, neutrophils are rapidly cleared from circulation through specialized efferocytic macrophages. Together with an intrinsic clock, these processes contribute to circadian fluctuations, preserving self-tolerance and protection against invading pathogens. However, metabolic perturbation of granulopoiesis and neutrophil homeostasis can result in low-grade chronic inflammation, as observed with aging. During acute pathogenic infections, hematopoiesis can also be switched into emergency mode, which has been recently associated with significant neutrophil functional heterogeneity. This review focuses on a new reassessment of regulatory mechanisms governing neutrophil production, life-cycle, and diversity in health and disease.
- Published
- 2019
43. Author response for 'Mesothelial cell CSF1 sustains peritoneal macrophage proliferation'
- Author
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Johanna Merlin, Marion I. Stunault, Marilyn Gros, Nathalie Vaillant, Alexandre Gallerand, Stoyan Ivanov, Rodolphe Guinamard, and Laurent Yvan-Charvet
- Subjects
Cancer research ,Biology ,Macrophage proliferation ,Mesothelial Cell - Published
- 2019
44. Immunometabolism of Phagocytes and Relationships to Cardiac Repair
- Author
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Russel Emmons, Laurent Yvan-Charvet, Edward B. Thorp, Esther Liu, Michael Abecassis, Amanda Becker, Gael Bories, Connor Lantz, and Shuang Zhang
- Subjects
0301 basic medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Myeloid ,Phagocyte ,Angiogenesis ,immunometabolism ,Ischemia ,Macrophage polarization ,Oxidative phosphorylation ,Review ,macrophage ,030204 cardiovascular system & hematology ,Biology ,Cardiovascular Medicine ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,medicine ,Innate immune system ,hypoxia ,phagocyte ,neutrophil ,medicine.disease ,3. Good health ,Cell biology ,reperfusion ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:RC666-701 ,cardiac repair ,Cardiology and Cardiovascular Medicine - Abstract
Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.
- Published
- 2019
45. Macrophage Origin, Metabolic Reprogramming and IL-1β Signaling: Promises and Pitfalls in Lung Cancer
- Author
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Laurent Yvan-Charvet, Emmanuel L. Gautier, Emma Guilbaud, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Gautier, Emmanuel, Université Nice Sophia Antipolis (... - 2019) (UNS), Programme ATIP - Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Review ,macrophage ,lcsh:RC254-282 ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,interleukin-1β and immunometabolism ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Blocking antibody ,interleukin-1 and immunometabolism ,Medicine ,Lung cancer ,Tumor microenvironment ,business.industry ,Immunotherapy ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lung adenocarcinoma ,3. Good health ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Adenocarcinoma ,immunotherapy ,[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy ,Signal transduction ,business - Abstract
International audience; Macrophages are tissue-resident cells that act as immune sentinels to maintain tissue integrity, preserve self-tolerance and protect against invading pathogens. Lung macrophages within the distal airways face around 8000⁻9000 L of air every day and for that reason are continuously exposed to a variety of inhaled particles, allergens or airborne microbes. Chronic exposure to irritant particles can prime macrophages to mediate a smoldering inflammatory response creating a mutagenic environment and favoring cancer initiation. Tumor-associated macrophages (TAMs) represent the majority of the tumor stroma and maintain intricate interactions with malignant cells within the tumor microenvironment (TME) largely influencing the outcome of cancer growth and metastasis. A number of macrophage-centered approaches have been investigated as potential cancer therapy and include strategies to limit their infiltration or exploit their antitumor effector functions. Recently, strategies aimed at targeting IL-1 signaling pathway using a blocking antibody have unexpectedly shown great promise on incident lung cancer. Here, we review the current understanding of the bridge between TAM metabolism, IL-1 signaling, and effector functions in lung adenocarcinoma and address the challenges to successfully incorporating these pathways into current anticancer regimens.
- Published
- 2019
46. Immunometabolic function of cholesterol in cardiovascular disease and beyond
- Author
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Giuseppe Danilo Norata, Laurent Yvan-Charvet, Rodolphe Guinamard, Fabrizia Bonacina, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Physiology ,[SDV]Life Sciences [q-bio] ,Inflammation ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Cardiovascular System ,Autoimmunity ,Immunomodulation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Physiology (medical) ,medicine ,Animals ,Humans ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Innate immune system ,Mevalonate kinase deficiency ,Cholesterol ,business.industry ,Inflammasome ,Acquired immune system ,medicine.disease ,3. Good health ,chemistry ,Cardiovascular Diseases ,Immune System ,Immunology ,medicine.symptom ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,business ,Energy Metabolism ,medicine.drug ,Signal Transduction - Abstract
Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann–Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing ‘metabolic’ drugs to modulate the immune response.
- Published
- 2019
- Full Text
- View/download PDF
47. Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis
- Author
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Sébastien Dussaud, Alexandre Boissonnas, Björn E. Clausen, Genevieve Marcelin, Emmanuel L. Gautier, Sophie Tran, Melissa Ouhachi, Lucie Poupel, Ines Baba, Philippe Lesnik, Thierry Huby, Elissa Magréau-Davy, Florian Sennlaub, Laurent Yvan-Charvet, Wilfried Le Goff, Adélaïde Gélineau, Martine Moreau, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center of the Johannes Gutenberg-University Mainz, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Institut de la Vision, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Johannes Gutenberg - Universität Mainz (JGU), Université Nice Sophia Antipolis (... - 2019) (UNS), Programme ATIP - Avenir, 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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), and CCSD, Accord Elsevier
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Ontogeny ,MESH: Cell Self Renewal ,Self renewal ,MESH: Monocytes ,MESH: Mice, Knockout ,Mice ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Immunology and Allergy ,Kupffer cells ,MESH: Animals ,Cell Self Renewal ,MESH: Lipid Metabolism ,Mice, Knockout ,Kupffer cell ,Lipids ,Research Highlight ,macrophages ,[SDV] Life Sciences [q-bio] ,Infectious Diseases ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,monocytes ,medicine.medical_specialty ,non-alcoholic steatohepatitis (NASH) ,Immunology ,Biology ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,MESH: Cell Proliferation ,Internal medicine ,medicine ,Animals ,Liver damage ,MESH: Mice ,Cell Proliferation ,MESH: Non-alcoholic Fatty Liver Disease ,Triglyceride storage ,Non alcoholic ,Lipid Metabolism ,medicine.disease ,MESH: Lipids ,eye diseases ,Mice, Inbred C57BL ,MESH: Kupffer Cells ,030104 developmental biology ,Endocrinology ,Steatohepatitis ,Homeostasis ,MESH: Liver - Abstract
International audience; Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C+ monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny.
- Published
- 2020
48. Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production
- Author
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Isabelle Dugail, Nemanja Vujic, Paul Dasilva-Jardine, Andrea E. Bochem, Kees Hovingh, Emmanuel L. Gautier, Fabienne Foufelle, Thibault Barouillet, François Orange, Madalina Duta-Mare, Manon Viaud, Laurent Yvan-Charvet, Lazaro Emilio Aira, Laurent Boyer, Christian Stehlik, Sandrine Marchetti, Edward B. Thorp, Stoyan Ivanov, Elsa Garcia, Dagmar Kratky, Rodolphe Guinamard, Isabelle Hainault, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,rac1 GTP-Binding Protein ,Erythrocytes ,Oxysterol ,Physiology ,Inflammasomes ,[SDV]Life Sciences [q-bio] ,Hypercholesterolemia ,Inflammation ,Apoptosis ,Mitochondrion ,Article ,Apoptotic cell clearance ,03 medical and health sciences ,Mice ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Macrophage ,Animals ,Lymphocytes ,Efferocytosis ,ComputingMilieux_MISCELLANEOUS ,Caspase ,Liver X Receptors ,biology ,Chemistry ,Hydrolysis ,Macrophages ,Neuropeptides ,Biological Transport ,Oxysterols ,Sterol Esterase ,Cell biology ,Mitochondria ,Mice, Inbred C57BL ,030104 developmental biology ,Cholesterol ,Receptors, LDL ,Splenomegaly ,biology.protein ,Cholesterol Esters ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Lysosomes - Abstract
Rationale: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. Objective: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. Methods and Results: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress–induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1–dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor–mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. Conclusions: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.
- Published
- 2018
49. Poststatin era in atherosclerosis management: lessons from epidemiologic and genetic studies
- Author
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Laurent Yvan-Charvet, Bertrand Cariou, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Aging ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Population ,Psychological intervention ,MEDLINE ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Leverage (negotiation) ,Genetics ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Pharmaceutical innovations ,education ,Molecular Biology ,Cause of death ,education.field_of_study ,Nutrition and Dietetics ,Public health ,Cell Biology ,Atherosclerosis ,3. Good health ,Poststatin ,Cardiology and Cardiovascular Medicine - Abstract
International audience; PURPOSE OF REVIEW: Cardiovascular diseases (CVD) are the leading cause of death worldwide with over 17 million deaths every year and represent a major public health challenge. The last decade has seen the emergence of novel antiatherogenic therapies. RECENT FINDINGS: Despite intensive lipid and blood pressure interventions, the burden of CVD is expected to markedly progress because of the global aging of the population and increasing exposure to detrimental lifestyle-related risk. Epidemiologic and genetic studies helped to better apprehend the biology of atherosclerosis and allowed pharmaceutical innovation and recent translational successes. This includes the development of novel lipid and glucose-lowering therapies and the leverage of anti-inflammatory therapies. SUMMARY: Here, we discuss promises and expectations of emerging scientific and pharmaceutical innovations and translational successes to meet the global therapeutic demand.
- Published
- 2018
50. Is defective cholesterol efflux an integral inflammatory component in myelopoiesis-driven cardiovascular diseases?
- Author
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Filip K. Swirski and Laurent Yvan-Charvet
- Subjects
0301 basic medicine ,Cholesterol ,business.industry ,Arthritis ,Pharmacology ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Component (UML) ,medicine ,Myelopoiesis ,Efflux ,Cardiology and Cardiovascular Medicine ,business - Published
- 2018
- Full Text
- View/download PDF
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