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1. Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Author

Dany Gaillard, David Masson, Erwan Garo, Maamar Souidi, Jean-Paul Pais de Barros, Kristina Schoonjans, Jacques Grober, Philippe Besnard, and Charles Thomas

Subjects
bile acids, cholesterol, hypercholesterolemia, LXR, FXR, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. Conclusions: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.

Published
2021
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2. Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis.

Author

Amélie Simon, Jean-François Subra, Philippe Guilpain, Pascale Jeannin, Pascale Pignon, Simon Blanchard, Erwan Garo, Sébastien Jaillon, Alain Chevailler, Gilles Renier, Xavier Puéchal, Barbara Bottazzi, Alberto Mantovani, Yves Delneste, and Jean-François Augusto

Subjects
Medicine, Science
Abstract

Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients.Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs.Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p

Published
2016
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4. IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNγ.

Author

Etienne D Foucher, Simon Blanchard, Laurence Preisser, Erwan Garo, Norbert Ifrah, Philippe Guardiola, Yves Delneste, and Pascale Jeannin

Subjects
Medicine, Science
Abstract

IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (Mφ) or dendritic cells (DC). A wide spectrum of Mφ and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) Mφ (IL-34-Mφ). Upon LPS stimulation, IL-34-Mφ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. IL-34-Mφ exhibit poor T cell costimulatory properties, and have potent immunosuppressive properties (decrease of TCR-stimulated T cell proliferation). For all the parameters analyzed, IL-34-Mφ are phenotypically and functionally similar to M-CSF-Mφ. IL-34 appears as efficient as M-CSF in inducing the generation of immunosuppressive Mφ. Moreover, the generation of IL-34-Mφ is mediated through the M-CSF receptor, is independent of endogenous M-CSF consumption and is potentiated by IL-6. In an attempt to identify strategies to prevent a deleterious M2 cell accumulation in some pathological situations, we observed that IFNγ and GM-CSF prevent the generation of immunosuppressive Mφ induced by IL-34. IFNγ also switches established IL-34-Mφ into immunostimulatory Mφ. In conclusion, we demonstrate that IL-34 drives the differentiation of monocytes into immunosuppressive M2, in a manner similar to M-CSF, and that IFNγ and GM-CSF prevent this effect.

Published
2013
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6. IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation.

Author

Murielle Corvaisier, Yves Delneste, Henry Jeanvoine, Laurence Preisser, Simon Blanchard, Erwan Garo, Emmanuel Hoppe, Benjamin Barré, Maurice Audran, Béatrice Bouvard, Jean-Paul Saint-André, and Pascale Jeannin

Subjects
Biology (General), QH301-705.5
Abstract

Interleukin-26 (IL-26), a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn's disease, suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin(+) fibroblast-like synoviocytes and CD68(+) macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20). Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t(+) Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R(-) or CCR6(-) CD161(-)) CD4(+) memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and chronic inflammatory disorders.

Published
2012
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7. Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Author

Erwan Garo, Charles Thomas, Kristina Schoonjans, Dany Gaillard, Maamar Souidi, Jacques Grober, Philippe Besnard, Jean-Paul Pais de Barros, David Masson, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University of Colorado Anschutz [Aurora], Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Radiobiologie des expositions accidentelles (IRSN/PSE-SANTE/SERAMED/LRAcc), Service de recherche en radiobiologie et en médecine régénérative (IRSN/PSE-SANTE/SERAMED), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire de Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Dijon, Institut Agro, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, Plateforme Lipidomique [Dijon] (LAP), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe NuTox (LNC - U1231) (NUTOX), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Muricholic acid, Drug Evaluation, Preclinical, Receptors, Cytoplasmic and Nuclear, Cholesterol, Dietary, chemistry.chemical_compound, 0302 clinical medicine, Biology (General), Spectroscopy, 2. Zero hunger, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Bile acid, Chemistry, General Medicine, 3. Good health, Computer Science Applications, Blot, medicine.anatomical_structure, Cholesterol, FXR, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), LXR, medicine.medical_specialty, Oxysterol, QH301-705.5, medicine.drug_class, Hypercholesterolemia, Article, Catalysis, Bile Acids and Salts, Inorganic Chemistry, 03 medical and health sciences, In vivo, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physical and Theoretical Chemistry, Liver X receptor, QD1-999, Molecular Biology, Organic Chemistry, Cholic Acids, Bile acids, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. Conclusions: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.

Published
2021

8. Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis

Author

Alberto Mantovani, Barbara Bottazzi, Jean Francois Subra, Philippe Guilpain, Pascale Pignon, Pascale Jeannin, Amelie Simon, Erwan Garo, Jean-François Augusto, Gilles Renier, Simon Blanchard, Yves Delneste, Xavier Puéchal, Sébastien Jaillon, Alain Chevailler, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers - Faculté de médecine (UA UFR Médecine), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Montpellier (UM), Laboratoire d'Immunologie et d'Allergologie, CHU d'Angers, PRES Université Nantes Angers Le Mans (UNAM), Département de Médecine Interne, Centre National de Référence Maladies Systémiques et Autoimmunes Rares, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), This work was supported by institutionalgrants from Institut National de la Santé et de laRecherche Médicale, France and the University ofAngers and by a grant from the Agence Nationale dela Recherche (project Pentraximmune). AmélieSimon and Sébastien Jaillon were supported bygrants from the Ministère de la Recherche et del’Enseignement supérieur (Bourse année-recherche)and the Conseil Général du Maine et Loire,respectively., and Bernardo, Elizabeth

Subjects
0301 basic medicine, Male, Pathology, Neutrophils, lcsh:Medicine, Apoptosis, Pathology and Laboratory Medicine, Biochemistry, White Blood Cells, 0302 clinical medicine, Proteinase 3, Animal Cells, Medicine and Health Sciences, Enzyme-Linked Immunoassays, lcsh:Science, skin and connective tissue diseases, Fluorescent Antibody Technique, Indirect, Staining, Multidisciplinary, biology, Cell Death, Middle Aged, Prognosis, 3. Good health, Serum Amyloid P-Component, C-Reactive Protein, Cell Processes, Myeloperoxidase, Female, Cellular Types, Microscopic polyangiitis, Granulomatosis with polyangiitis, Vasculitis, Research Article, Adult, medicine.medical_specialty, Immune Cells, Inflammatory Diseases, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Enzyme-Linked Immunosorbent Assay, Research and Analysis Methods, Autoimmune Diseases, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Rheumatology, medicine, Humans, cardiovascular diseases, Wegener Granulomatosis, Immunoassays, Cytoplasmic Staining, Anti-neutrophil cytoplasmic antibody, Autoantibodies, 030203 arthritis & rheumatology, Blood Cells, business.industry, lcsh:R, Autoantibody, Biology and Life Sciences, Cell Biology, medicine.disease, 030104 developmental biology, Specimen Preparation and Treatment, Case-Control Studies, biology.protein, Immunologic Techniques, lcsh:Q, Clinical Immunology, Clinical Medicine, business, Biomarkers
Abstract

Objectives Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Methods Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs. Results Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p

Published
2016

9. Quantitative ultrasonic tissue characterization as a new tool for continuous monitoring of chronic liver remodelling in mice

Author

Alwyn P. D'sa, Erwan Garo, Marius Teletin, Jean-Luc Vonesch, Mohamed Selloum, Alain Guimond, Marie-France Champy, Laurent Monassier, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Liver Cirrhosis, Male, Pathology, Time Factors, 030218 nuclear medicine & medical imaging, Mice, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, MESH: Collagen, MESH: Animals, Carbon Tetrachloride, Ultrasonography, 0303 health sciences, Ultrasound, MESH: Reproducibility of Results, Liver, Disease Progression, MESH: Disease Progression, Female, Collagen, MESH: Liver Cirrhosis, medicine.medical_specialty, CCL4, Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, In vivo, Image Interpretation, Computer-Assisted, medicine, Animals, MESH: Mice, Ligation, 030304 developmental biology, Hepatology, business.industry, MESH: Carbon Tetrachloride, MESH: Time Factors, Reproducibility of Results, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Ligation, medicine.disease, MESH: Male, Intensity (physics), Mice, Inbred C57BL, Disease Models, Animal, chemistry, Carbon tetrachloride, Bile Ducts, MESH: Bile Ducts, MESH: Disease Models, Animal, Densitometry, business, MESH: Female, MESH: Image Interpretation, Computer-Assisted, MESH: Ultrasonography, MESH: Liver
Abstract

BACKGROUND/AIM: Recognition of the limitations of liver biopsies has led to the need for non-invasive tests to assess liver fibrosis from intensity and kinetic point of views. The aim of the present study was to evaluate non-invasive ultrasonic tissue characterization for the continuous monitoring of this process in mice. METHODS: Twelve-week-old male and female C57Bl6/J mice were submitted to repetitive carbon-tetrachloride (CCl4) intraperitoneal injections during 8 weeks or analysed 28 days after common bile duct ligation (BDL). The extent and kinetic of the disease progression were followed by the measurement of ultrasound backscatter intensity. This was compared with histological and blood parameter analysis. RESULTS: CCl4 induced a progressive increase in in vivo liver tissue backscatter intensity in both males and females. This increase was mainly correlated with interstitial fibrosis and, to a lower extent, with nuclear surface of the hepatocytes. A similar result was found after BDL. CONCLUSIONS: These data demonstrate for the first time in a systematic study that ultrasound tissue characterization can be used as a reliable tool to follow liver remodelling in mice continuously.

Published
2007

10. IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells

Author

Paul Calès, Elodie Beaumont, Hélène Le Guillou-Guillemette, Philippe Roingeard, Françoise Lunel-Fabiani, Jérôme Boursier, Laurence Preisser, Pascale Jeannin, Erwan Garo, Isabelle Frémaux, Yves Delneste, Charline Miot, Etienne D. Foucher, Isabelle Fouchard, Anne Croue, Simon Blanchard, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), and Université d'Angers (UA)

Subjects
Adult, Liver Cirrhosis, Male, Macrophage colony-stimulating factor, Chemokine, [SDV]Life Sciences [q-bio], Biology, Collagen Type I, Cell Line, Proinflammatory cytokine, Interferon-gamma, Fibrosis, Hepatic Stellate Cells, medicine, Humans, Aged, Interleukin-13, Hepatology, Interleukins, Macrophage Colony-Stimulating Factor, Monocyte, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Case-Control Studies, Immunology, Hepatocytes, Interleukin 34, Cancer research, biology.protein, Hepatic stellate cell, Female, Matrix Metalloproteinase 1, Hepatic fibrosis
Abstract

International audience; Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mφ) remain poorly defined. We report that chronically HCV-infected patients with high fibrosis stages have higher serum levels of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)−34 than HCV-infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL-34 and M-CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL-34 and M-CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mφ generated with M-CSF (M-CSF-Mφ) or IL-34 (IL-34-Mφ). M-CSF and IL-34 up-regulate the expression, by differentiating monocytes, of chemokine (C-C motif) ligand (CCL)2, CCL4, C-C chemokine receptor (CCR)1, and CCR5, which are involved in monocyte recruitment/Mφ accumulation in liver lesions. M-CSF-Mφ and IL-34-Mφ also express the hepatic stellate cell (HSC) activators, platelet-derived growth factor, transforming growth factor beta, and galectin-3. IL-34-Mφ and M-CSF-Mφ induce type I collagen synthesis by HSCs, the main collagen-producing cells in liver fibrosis. IL-13, whose expression correlates with the fibrosis stage in HCV-infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL-34-Mφ and M-CSF-Mφ, thereby enhancing collagen synthesis. By inhibiting the production of interferon-gamma (IFN-γ) by activated natural killer cells, IL-34-Mφ and M-CSF-Mφ prevent the IFN-γ-induced killing of HSCs. Conclusion: These results identify M-CSF and IL-34 as potent profibrotic factors in HCV liver fibrosis.

Published
2014

11. Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients

Author

Sébastien Jaillon, Barbara Bottazzi, Erwan Garo, Alberto Mantovani, Yveline Hamon, Sarah Ghamrawi, Thierry Urban, Jean Francois Subra, Christine Person, Yves Delneste, Jean-Philippe Bouchara, Pascale Jeannin, Jean Louis Giniès, Université d'Angers (UA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], PRES Université Nantes Angers Le Mans (UNAM), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), and Univ Angers, Okina

Subjects
Male, [SDV]Life Sciences [q-bio], Cystic fibrosis, Aspergillus fumigatus, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, pentraxin 3, Child, 0303 health sciences, COPD, biology, Pancreatic Elastase, Elastase, PTX3, Blood Proteins, 3. Good health, [SDV] Life Sciences [q-bio], Serum Amyloid P-Component, Infectious Diseases, medicine.anatomical_structure, C-Reactive Protein, Pseudomonas aeruginosa, Female, medicine.symptom, Adult, Proteases, Adolescent, Immunology, Respiratory Mucosa, Opportunistic Infections, Microbiology, 03 medical and health sciences, Young Adult, Bacterial Proteins, medicine, Humans, elastase, Pseudomonas Infections, Molecular Biology, 030304 developmental biology, Immune Evasion, Lung, business.industry, Sputum, Cell Biology, biology.organism_classification, medicine.disease, Immunity, Innate, Proteolysis, Pulmonary Aspergillosis, business, 030215 immunology
Abstract

International audience; The prototypic long pentraxin PTX3, a soluble pattern recognition receptor, plays an important role in innate defense against selected pathogens by favoring their elimination and the initiation of protective responses. PTX3 has notably beneficial effects in mice infected with Aspergillus fumigatus and Pseudomonas aeruginosa. Cystic fibrosis (CF), a severe inherited autosomal recessive disease, is characterized by recurrent lung infections, especially by these two pathogens. We thus hypothesized that the status of PTX3 may be altered in CF patients. Level and integrity of PTX3 were analyzed in the sputum samples from 51 CF patients and 7 patients with chronic obstructive pulmonary disease (COPD). The levels of PTX3 were increased in serums from CF patients, but low in their respiratory secretions. PTX3 concentrations in sputum samples were dramatically lower in CF patients than in COPD patients. The low concentration of PTX3 resulted from a proteolysis cleavage by elastase and A. fumigatus proteases. Interestingly, the N-ter domain of PTX3, involved in protection against A. fumigatus, is preferentially degraded by these proteases. These results indicate that the selective proteolysis of PTX3 in the CF lung may explain, in part, the recurrent lung infections by PTX3-sensitive pathogens in CF patients.

Published
2013

12. IL-34 Induces the Differentiation of Human Monocytes into Immunosuppressive Macrophages. Antagonistic Effects of GM-CSF and IFNγ

Author

Laurence Preisser, Philippe Guardiola, Simon Blanchard, Norbert Ifrah, Etienne D. Foucher, Erwan Garo, Yves Delneste, Pascale Jeannin, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), PRES Université Nantes Angers Le Mans (UNAM), Service des maladies du sang [Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), SNP, Transcriptome & Epigénomique [CHU Angers] (Plateforme STE), ligue contre le Cancer (Équipe labellisée 2012–2014)., and Blanchard, Simon

Subjects
Chemokine, lcsh:Medicine, Monocytes, 0302 clinical medicine, Cluster Analysis, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, Cell Differentiation, Interleukin-12, Interleukin-10, Interleukin 10, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Interleukin 12, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Receptors, Chemokine, Chemokines, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immune Cells, Immunology, Receptor, Macrophage Colony-Stimulating Factor, Immune Suppression, Immunomodulation, 03 medical and health sciences, Interferon-gamma, medicine, Humans, Biology, 030304 developmental biology, CD86, Monocyte, Gene Expression Profiling, Interleukins, Macrophages, lcsh:R, Immunity, Immunoregulation, Granulocyte-Macrophage Colony-Stimulating Factor, Immune System, biology.protein, Interleukin 34, lcsh:Q, CD80, Developmental Biology
Abstract

International audience; IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (MQ) or dendritic cells (DC). A wide spectrum of MQ and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14 high CD163 high CD1a 2 MQ (IL-34-MQ). Upon LPS stimulation, IL-34-MQ exhibit an IL-10 high IL-12 low M2 profile and express low levels of the costimulatory molecules CD80 and CD86. IL-34-MQ exhibit poor T cell costimulatory properties, and have potent immunosuppressive properties (decrease of TCR-stimulated T cell proliferation). For all the parameters analyzed, IL-34-MQ are phenotypically and functionally similar to M-CSF-MQ. IL-34 appears as efficient as M-CSF in inducing the generation of immunosuppressive MQ. Moreover, the generation of IL-34-MQ is mediated through the M-CSF receptor, is independent of endogenous M-CSF consumption and is potentiated by IL-6. In an attempt to identify strategies to prevent a deleterious M2 cell accumulation in some pathological situations, we observed that IFNc and GM-CSF prevent the generation of immunosuppressive MQ induced by IL-34. IFNc also switches established IL-34-MQ into immunostimulatory MQ. In conclusion, we demonstrate that IL-34 drives the differentiation of monocytes into immunosuppressive M2, in a manner similar to M-CSF, and that IFNc and GM-CSF prevent this effect.

Published
2013

13. IL-26 Kick-Starts Rheumatoid Arthritis

Author

Laurence Preisser, Maurice Audran, Erwan Garo, Yves Delneste, Emmanuel Hoppé, Benjamin Barré, Henry Jeanvoine, Jean-Paul Saint-André, Béatrice Bouvard, Simon Blanchard, Pascale Jeannin, Murielle Corvaisier, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Immunologie et d'Allergologie, CHU d'Angers, PRES Université Nantes Angers Le Mans (UNAM), Groupe d'Études Remodelage Osseux et bioMatériaux (GEROM), Université d'Angers (UA), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), and Univ Angers, Okina

Subjects
Male, Chemokine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Interleukin-1beta, Inflammatory bowel disease, Memory T cells, Monocytes, Arthritis, Rheumatoid, 0302 clinical medicine, Synovial Fluid, Myeloid Cells, Biology (General), 0303 health sciences, General Neuroscience, Interleukin-17, Synovial Membrane, Middle Aged, Immunohistochemistry, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cytokine, Synopsis, Medicine, Cytokines, Tumor necrosis factor alpha, Female, Interleukin 17, medicine.symptom, Inflammation Mediators, General Agricultural and Biological Sciences, Research Article, QH301-705.5, Immune Cells, Immunology, T cells, Inflammation, Bone Marrow Cells, Immunopathology, Biology, General Biochemistry, Genetics and Molecular Biology, Proinflammatory cytokine, 03 medical and health sciences, Rheumatology, medicine, Humans, Rheumatoid arthritis, Secretion, 030304 developmental biology, Demography, General Immunology and Microbiology, Interleukins, Models, Immunological, Immunity, Fibroblasts, CCL20, Immune System, biology.protein, Th17 Cells, Joints, Synovial membrane, Immunologic Memory, 030215 immunology
Abstract

Human interleukin-26 induces Th17 cells, is over-expressed in rheumatoid arthritis, and is thus a promising therapeutic target in chronic inflammatory disease., Interleukin-26 (IL-26), a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn's disease, suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin+ fibroblast-like synoviocytes and CD68+ macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20). Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t+ Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R− or CCR6− CD161−) CD4+ memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and chronic inflammatory disorders.

Published
2012

14. The Tachykinins Substance P and Hemokinin-1 Favor the Generation of Human Memory Th17 Cells by Inducing IL-1β, IL-23, and TNF-Like 1A Expression by Monocytes

Author

Erwan Garo, Murielle Corvaisier, Mari Scotet, Simon Blanchard, Pierre Cunin, Antoine Caillon, Yves Delneste, Pascale Jeannin, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), PRES Université Nantes Angers Le Mans (UNAM), Ligue contre le Cancer (Équipe labellisée 2008–2010)Ligue contre le Cancer (Comité du Maine et Loire)Association pour la Recherche sur le Cancer (ARC), and Blanchard, Simon

Subjects
Tumor Necrosis Factor Ligand Superfamily Member 15, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Cell, Interleukin-1beta, Substance P, Cell Communication, Biology, Interleukin-23, Monocytes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Downregulation and upregulation, Tachykinins, Tachykinin receptor 1, medicine, Immunology and Allergy, Humans, IL-2 receptor, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Monocyte, Cell Polarity, Cell Differentiation, Cell biology, medicine.anatomical_structure, chemistry, Th17 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, Inflammation Mediators, Immunologic Memory, 030215 immunology
Abstract

The nervous system influences immune responses through the release of neural factors such as neuropeptides. Among them, the tachykinin substance P (SP) signals via the neurokinin 1 receptor (NK-1R), which is expressed by various immune cells. We thereby analyzed in this paper whether tachykinins may participate in human CD4+ Th cell polarization. We report that SP and hemokinin-1 (HK-1) upregulate IL-17A and IFN-γ production by human memory CD4+ T cells without affecting IL-4 and IL-10 production. SP and HK-1 switch non–Th17-committed CD4+ memory T cells into bona fide Th17 cells and Th1/Th17 cells. In contrast, SP and HK-1 do not modulate the polarization of naive CD4+ T cells. SP- and HK-1–induced Th17 cell generation is mediated through NK-1R and requires the presence of monocytes. SP and HK-1 trigger IL-1β, IL-6, and TNF-α production, upregulate IL-23 production, and enhance TNF-like 1A expression on monocyte surface. Neutralization experiments demonstrated that IL-1β, IL-23, and TNF-like 1A are involved in the SP- and HK-1–induced Th17 cell. The other members of the tachykinin family, neurokinins A and B, have no effect on the differentiation of naive and memory T cells. These results thereby show that SP and HK-1 are novel Th17 cell-inducing factors that may act locally on memory T cells to amplify inflammatory responses.

Published
2011

15. The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice

Author

Judy McNeilly, Mohamed Benahmed, Patrick Fénichel, Kristina Schoonjans, Erwan Garo, Johan Auwerx, David H. Volle, Mélanie Decourteix, Alan S. McNeilly, 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)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'endocrinologie [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Communication Cellulaire en Biologie de la Reproduction, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physique et Physiologie Intégratives de l’Arbre en environnement Fluctuant - Clermont Auvergne (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, 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)-Université Côte d'Azur (UCA)

Subjects
Acute Regulatory Protein, Male, Retinoic Acid, Diethylstilbestrol, Receptors, Cytoplasmic and Nuclear, Estrogen receptor, Apoptosis, Adult Male-Rat, Histones, Mice, 0302 clinical medicine, Pregnancy, Testis, Testosterone, Efferent Ductules, ComputingMilieux_MISCELLANEOUS, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis, Mice, Knockout, Medicine(all), 0303 health sciences, Estradiol, Negative Feedback-Regulation, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Transcriptional Activity, Small heterodimer partner, Female, Germ cell, Research Article, medicine.drug, Estrogen-Receptor, medicine.medical_specialty, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Methylation, Models, Biological, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Retinoids, 03 medical and health sciences, Internal medicine, medicine, Animals, RNA, Messenger, Spermatogenesis, Liver X receptor, Infertility, Male, 030304 developmental biology, Liver-X Receptor, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Germ-Cell Fate, Mice, Inbred C57BL, Endocrinology, Animals, Newborn, Nuclear receptor, Estrogen, Bile-Acid Synthesis
Abstract

Studies in rodents have shown that male sexual function can be disrupted by fetal or neonatal administration of compounds that alter endocrine homeostasis, such as the synthetic nonsteroidal estrogen diethylstilbestrol (DES). Although the molecular basis for this effect remains unknown, estrogen receptors likely play a critical role in mediating DES-induced infertility. Recently, we showed that the orphan nuclear receptor small heterodimer partner (Nr0b2), which is both a target gene and a transcriptional repressor of estrogen receptors, controls testicular function by regulating germ cell entry into meiosis and testosterone synthesis. We therefore hypothesized that some of the harmful effects of DES on testes could be mediated through Nr0b2. Here, we present data demonstrating that Nr0b2 deficiency protected mice against the negative effects of DES on testis development and function. During postnatal development, Nr0b2-null mice were resistant to DES-mediated inhibition of germ cell differentiation, which may be the result of interference by NOW with retinoid signals that control meiosis. Adult Nr0b2-null male mice were also protected against the effects of DES; however, we suggest that this phenomenon was due to the removal of the repressive effects of Nr0b2 on steroidogenesis. Together, these data demonstrate that Nr0b2 plays a critical role in the pathophysiological changes induced by DES in the mouse testis.

Published
2009

16. PolyI:C plus IL-2 or IL-12 induce IFN-γ production by human NK cells via autocrine IFN-β

Author

Fang Tan, Branka Horvat, Erwan Garo, Isabelle Frémaux, Pascale Jeannin, Pierre Eid, Mari Scotet, Yves Delneste, Dorothée Duluc, Simon Blanchard, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), PRES Université Nantes Angers Le Mans (UNAM), Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Greffes d'Epitheliums et Regulation de l'Activation Lymphocytaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Paul Brousse, Ligue contre le Cancer (Équipe labellisée 2008–2010), École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and Blanchard, Simon

Subjects
Interferon-Induced Helicase, IFIH1, Gene Expression, Receptor, Interferon alpha-beta, NK cells, DEAD-box RNA Helicases, Mice, 0302 clinical medicine, Immunology and Allergy, STAT1, Phosphorylation, Receptor, STAT4, Cells, Cultured, Mice, Knockout, 0303 health sciences, PolyI:C, Receptors, Interleukin-12, STAT4 Transcription Factor, Interleukin-12, Killer Cells, Natural, Autocrine Communication, STAT1 Transcription Factor, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Type I IFN, Mice, Inbred Strains, Biology, Antibodies, Cell Line, IFN-gamma, Interferon-gamma, 03 medical and health sciences, Immune system, Animals, Humans, Autocrine signalling, 030304 developmental biology, Interferon-beta, Molecular biology, Toll-Like Receptor 3, Kinetics, Poly I-C, Cell culture, TLR3, biology.protein, Interleukin-2, 030215 immunology
Abstract

International audience; NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-gamma induced by polyI:C plus IL-2/IL-12. Similarly, IFN-gamma production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 -/- compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-gamma production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-gamma and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.

Published
2009

17. Long-term consequences of Hodgkin lymphoma therapy on T-cell lymphopoiesis

Author

Isabelle Pellier, Elsa Berardi, Emilie De Carli, Marie Audrain, Martine Gardembas, Gilles Renier, Yves Delneste, Stéphanie Proust-Houdemont, Yves Reguerre, Aline Tanguy-Schmidt, Josué Rakotonjanahary, Martine Georgin-Mege, Simon Blanchard, Alain Fischer, Aline Clavert, Erwan Garo, Marie Pierre Moles, Pascale Jeannin, Capucine Picard, and Charline Miot

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, Oncology, medicine.medical_specialty, Pathology, T cell, Immunology, Antineoplastic Agents, Thymus Gland, CD8-Positive T-Lymphocytes, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Immunology and Allergy, Prospective Studies, Lymphopoiesis, Neoplasm Staging, 030304 developmental biology, B-Lymphocytes, 0303 health sciences, business.industry, Middle Aged, Hodgkin Disease, Term (time), Killer Cells, Natural, medicine.anatomical_structure, Gamma Rays, Hodgkin lymphoma, Female, Neoplasm staging, business, 030215 immunology
Published
2015

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