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7 results on '"Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland]"'

1. Hydrogen Peroxide Affects Growth of S. aureus Through Downregulation of Genes Involved in Pyrimidine Biosynthesis

Author

Buvelot, Hélène, Roth, Myriam, Jaquet, Vincent, Lozkhin, Andrey, Renzoni, Adriana, Bonetti, Eve-Julie, Gaia, Nadia, Laumay, Floriane, Mollin, Michéle, Stasia, Marie-José, Schrenzel, Jacques, François, Patrice, Krause, Karl-Heinz, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Service of Infectious Diseases [Geneva, Switzerland], Geneva University Hospital (HUG), Service of infectious diseases, Hôpitaux Universitaires de Genève (HUG), CGD Diagnosis and Research Centre (CDiReC), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre Diagnostic et Recherche sur la Granulomatose septique chronique (CDiReC), CHUGA, University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], and Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes)

Subjects
Staphylococcus aureus, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Immunology, Down-Regulation, hydrogen peroxide, Gene Expression Regulation, Bacterial, S. aureus, pyrimidine metabolism, Pyrimidines, Bacterial Proteins, neutrophils, carA, Immunology and Allergy, Humans, Reactive Oxygen Species, Cells, Cultured, Original Research
Abstract

International audience; Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus , as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H 2 O 2 ). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA , a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H 2 O 2 . The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA . As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus , allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.

Published
2021

2. IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

Author

Géraldine Bart, Benoit Le Goff, Pierre Layrolle, Cem Gabay, Frédéric Blanchard, Gaby Palmer, Aurélie Najm, Régis Brion, S Touchais, Valérie Trichet, Marie-Astrid Boutet, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe Labellisée LIGUE 2012 [Nantes], Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Division of Rheumatology [Geneva, Switzerland], Geneva University Hospital, Geneva-Department of Internal Medicine [Genève], This work was supported by Inserm and in part by the Arthritis Foundation and by the French Society of Rheumatology. M-AB was a recipient from a fellowship from the French Ministry of Research. CG is supported by grants from the Swiss National Science Foundation (310030_152638), the Rheumasearch Foundation, the Uniscientia Foundation and the Institute of Arthritis Research., maurice, sandrine, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland]

Subjects
Cartilage, Articular, 0301 basic medicine, medicine.medical_treatment, Arthritis, Macrophages/immunology, Interleukin-23, Arthritis, Rheumatoid, Mice, 0302 clinical medicine, Tumor Necrosis Factor-alpha/genetics/immunology, Immunology and Allergy, ddc:616, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Interleukin-17, Synovial Membrane, Interleukin, Arthritis, Experimental/genetics/immunology, Immunohistochemistry, Interleukin-17/genetics/immunology, 3. Good health, Synovial Membrane/cytology, medicine.anatomical_structure, Cytokine, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Cytokines, Tumor necrosis factor alpha, Arthritis, Rheumatoid/immunology, Blotting, Western, Immunology, Enzyme-Linked Immunosorbent Assay, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, In Vitro Techniques, Real-Time Polymerase Chain Reaction, Bone and Bones, Interleukin-6/genetics/immunology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Proinflammatory cytokine, 03 medical and health sciences, Rheumatology, Fibroblasts/immunology, medicine, Animals, Humans, Th17 Cells/immunology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Inflammation, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, Interleukins, Macrophages, Cartilage, Bone and Bones/diagnostic imaging, X-Ray Microtomography, Fibroblasts, Interleukins/genetics/immunology, medicine.disease, Arthritis, Experimental, Cartilage, Articular/diagnostic imaging, 030104 developmental biology, Interleukin-23/genetics/immunology, Cell culture, Culture Media, Conditioned, Th17 Cells, Transcriptome, business
Abstract

International audience; OBJECTIVES:Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.METHODS:Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.RESULTS:Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.CONCLUSIONS:This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.

Published
2017

3. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

Author

Mahdia Benkhoucha, Mashal Claude Ahmed, Dominique Baeten, Romain Marignier, Jose Boucraut, Olivier Casez, Michael Hahne, Jean Boutonnat, Corinne Sonrier, Benoit Manfroi, Laurie Baert, Patrice N. Marche, Nathalie Sturm, Marine Tessier, Patrice H. Lalive, Romain R. Vivès, Bertrand Huard, Cyril Rivat, Catherine Ghezzi, Hans Lassmann, Pascal Schneider, Natalia Popa, Gilda Raguenez, Alexis Broisat, Hugues Lortat-Jacob, Mitra Ahmadi, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Department of Clinical Immunology and Rheumatology [Academic Medical Center, Amsterdam], University of Amsterdam [Amsterdam] (UvA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), University of Vienna [Vienna], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], This work was supported by Grenoble Alpes University (B.H.), the National Institute of Health and Medical Research (B.H.), the Association for Aid to Multiple Sclerosis Research (B.H.), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, B.H.), the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 to PL), and the Swiss Multiple Sclerosis Society (P.L.)., Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Lausanne = University of Lausanne (UNIL), Grenoble Alpes University, the National Institute of Health and Medical Research, the Association for Aid to Multiple Sclerosis Research), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 )The Swiss Multiple Sclerosis Society, and MARCHE, Patrice

Subjects
Male, 0301 basic medicine, T-Lymphocytes, Mice, chemistry.chemical_compound, 0302 clinical medicine, B-Cell Activating Factor, Medicine, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Chondroitin Sulfates, Middle Aged, Immunohistochemistry, Interleukin-10, 3. Good health, Interleukin 10, Neurology, Adult, Aged, Animals, Astrocytes/immunology, Astrocytes/metabolism, Astrocytes/pathology, B-Cell Activating Factor/metabolism, Cell Proliferation, Chondroitin Sulfate Proteoglycans/metabolism, Chondroitin Sulfates/metabolism, Cytokines/immunology, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental/immunology, Encephalomyelitis, Autoimmune, Experimental/metabolism, Encephalomyelitis, Autoimmune, Experimental/pathology, Female, Humans, Interleukin-10/immunology, Macrophages/pathology, Multiple Sclerosis/immunology, Multiple Sclerosis/metabolism, Multiple Sclerosis/pathology, T-Lymphocytes/immunology, Tumor Necrosis Factor Ligand Superfamily Member 13/genetics, Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism, Tumor Necrosis Factor Ligand Superfamily Member 13/pharmacology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, medicine.symptom, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Tumor Necrosis Factor Ligand Superfamily Member 13, Inflammation, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, B-cell activating factor, Autoimmune encephalitis, business.industry, Macrophages, Multiple sclerosis, medicine.disease, 030104 developmental biology, Chondroitin Sulfate Proteoglycans, chemistry, Chondroitin sulfate proteoglycan, Astrocytes, Immunology, Cytokine secretion, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.

Published
2019

4. IL-27-Induced Type 1 Regulatory T-Cells Produce Oxysterols that Constrain IL-10 Production

Author

Vigne , Solenne, Chalmin , Fanny, Duc , Donovan, Clottu , Aurélie S, Apetoh , Lionel, Lobaccaro , Jean-Marc A, Christen , Isabelle, Zhang , Juan, Pot , Caroline, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Pathology and Immunology [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Lipides - Nutrition - Cancer [Dijon - U1231] (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, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Novartis Institutes for BioMedical Research (NIBR), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), 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 ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Génétique, Reproduction et Développement - Clermont Auvergne ( GReD ), IFR79-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institutes for BioMedical Research, Novartis, 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)

Subjects
type 1 regulatory T cells, Epstein–Barr virus-induced G-protein coupled receptor 2 (EBI2), Immunology, autoimmunity, immunometabolism, nuclear hormone liver X receptor, cholesterol 25-hydroxylase, ddc:616.07, CD4+ T cells, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, oxysterols, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Original Research
Abstract

IF 6.429; International audience; The behaviors of lymphocytes, including CD4(+) T helper cells, are controlled on many levels by internal metabolic properties. Lipid metabolites have recently been ascribed a novel function as immune response modulators and perturbation of steroids pathways modulates inflammation and potentially promotes a variety of diseases. However, the impact of lipid metabolism on autoimmune disease development and lymphocyte biology is still largely unraveled. In this line, oxysterols, oxidized forms of cholesterol, have pleiotropic roles on the immune response aside from their involvements in lipid metabolism. The oxysterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC) regulate antiviral immunity and immune cell chemotaxis. However, their physiological effects on adaptive immune response in particular on various subset CD4(+) T lymphocytes are largely unknown. Here, we assessed oxysterol levels in subset of CD4(+) T cells and demonstrated that 25-OHC and transcript levels of its synthesizing enzyme, cholesterol 25-hydroxylase, were specifically increased in IL-27-induced type 1 regulatory T (TR1) cells. We further showed that 25-OHC acts as a negative regulator of TR1 cells in particular of IL-10 secretion via liver X receptor signaling. Not only do these findings unravel molecular mechanisms accounting for IL-27 signaling but also they highlight oxysterols as pro-inflammatory mediators that dampens regulatory T cell responses and thus unleash a pro-inflammatory response.

Published
2017

5. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease

Author

Peter Lamprecht, Thierry Schaeverbeke, Hendrik Schulze-Koops, Eugen Feist, Jürgen Rech, Bernhard Hellmich, Eduardo Schiffrin, Delphine S. Courvoisier, Jacques Morel, Thierry Martin, Eric Hachulla, Bruno Fautrel, Andrew Sleight, Cem Gabay, Ina Kötter, Mohamed Hamidou, François Spertini, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Division of Rheumatology [Geneva, Switzerland], Geneva University Hospital, Geneva-Department of Internal Medicine [Genève], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Immunology and Allergy [Lausanne, Suisse], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Internal Medicine II, University of Tübingen, Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Rhumatologie Bordeaux (SERVICE DE RHUMATOLOGIE), CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Degauque, Nicolas, Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Service de Rhumatologie [CHU Pitié Salpêtrière], 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), and Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Injections, Subcutaneous, Immunology, Disease, Severity of Illness Index, Drug Administration Schedule, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Team4, Rheumatology, Prednisone, Internal medicine, medicine, Clinical endpoint, Humans, Immunology and Allergy, CRTI, Adverse effect, ComputingMilieux_MISCELLANEOUS, ddc:616, 030203 arthritis & rheumatology, Dose-Response Relationship, Drug, biology, business.industry, C-reactive protein, Interleukin-18, Interleukin, Middle Aged, Antirheumatic Agents/administration & dosage, Antirheumatic Agents/adverse effects, Antirheumatic Agents/therapeutic use, Biomarkers/blood, Female, Intercellular Signaling Peptides and Proteins/administration & dosage, Intercellular Signaling Peptides and Proteins/adverse effects, Intercellular Signaling Peptides and Proteins/therapeutic use, Interleukin-18/blood, Still's Disease, Adult-Onset/drug therapy, Still's Disease, Adult-Onset/immunology, Treatment Outcome, adult onset still’s disease, inflammation, juvenile idiopathic arthritis, 3. Good health, Clinical trial, Institutional repository, 030104 developmental biology, Antirheumatic Agents, biology.protein, Intercellular Signaling Peptides and Proteins, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Still's Disease, Adult-Onset, Biomarkers, medicine.drug
Abstract

Objectives Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. Methods In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. Results Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. Conclusions Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. Trial registration number NCT02398435.

Published
2018

6. Cx26 regulates proliferation of repairing basal airway epithelial cells

Author

Marc Bacchetta, S. Huang, Sophie Crespin, Jean-Sylvain Lacroix, Tecla Dudez, Jessica Bellec, P. Tantilipikorn, J. Bou Saab, Marc Chanson, Ludovic Wiszniewski, Brenda R. Kwak, T.H. Nguyen, laboratory of clinical investigation III [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Mahidol University [Bangkok, Thailand], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Internal Medicine Specialties [Geneva, Switzerland], Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Division of Otho-Rhino-Laryngology [Geneva, Switzerland], Geneva University Hospitals - HUG [Switzerland], Epithelix SARL [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE), Swiss National Science Foudation (grants 310000_119739 and 310030_134907/1)., Vaincre la Mucoviscidose., Téléthon Action Suisse., Novartis Stiftung für Medizinisch Biologische Forschung., and Le Bihan, Sylvie

Subjects
Population, Proliferation, Kruppel-Like Transcription Factors, Bronchi, Respiratory Mucosa, ddc:616.07, Biology, Biochemistry, Connexins, Cystic fibrosis, Cx26, Kruppel-Like Factor 4, 03 medical and health sciences, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, Humans, Gene silencing, Progenitor cell, Mucilair, education, Cells, Cultured, Gap junctions, Cell Proliferation, 030304 developmental biology, 0303 health sciences, education.field_of_study, ddc:618, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cell growth, Cell Differentiation, Epithelial Cells, Cell Biology, Epithelium, Cell biology, Connexin 26, medicine.anatomical_structure, KLF4, 030220 oncology & carcinogenesis, Immunology, cardiovascular system, Respiratory epithelium, Immortalised cell line, Repair, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation. Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs. We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation. This article is part of a Directed Issue entitled: Cystic fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.

Published
2014

7. Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner

Author

Pierre Boulanger, Sophie Crespin, Marc Chanson, Marc Bacchetta, Tecla Dudez, T.H. Nguyen, Saw See Hong, Thilo Köhler, Davide Losa, Christian van Delden, Jessica Bellec, Sandrine Morel, laboratory of clinical investigation III [Geneva, Switzerland], Geneva University Hospitals - HUG [Switzerland]-University of Geneva [Switzerland], Service of Infectious Diseases [Geneva, Switzerland], Geneva University Hospital (HUG), Department of Microbiology and Molecular Medicine Geneva [Switzerland], University of Geneva [Switzerland]-School of Medicine, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Swiss National Science Foundation Grants 310030_134907/1 and 32473B_140929., Vaincre la Mucoviscidose., Italian Cystic Fibrosis Research Foundation Grant 19/2009 (adopted by Fondazione Ricerca Fibrosi Cistica delegation La Bottega delle Donne)., Fondation pour des Bourses d’Etudes Italo-Suisses, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Le Bihan, Sylvie, Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], and Université de Genève = University of Geneva (UNIGE)-School of Medicine

Subjects
Cystic Fibrosis, MAP Kinase Kinase 4, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Immunology, Cystic Fibrosis Transmembrane Conductance Regulator, Inflammation, Apoptosis, Respiratory Mucosa, Cell Communication, ddc:616.07, Biology, p38 Mitogen-Activated Protein Kinases, Cell Line, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, medicine, Immunology and Allergy, Humans, Pseudomonas Infections, 030304 developmental biology, ddc:616, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ddc:618, Innate immune system, Gap Junctions, Epithelial Cells, respiratory system, 3. Good health, Cell biology, Cell culture, 030220 oncology & carcinogenesis, Connexin 43, Pseudomonas aeruginosa, Respiratory epithelium, medicine.symptom, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Chronic infection and inflammation of the airways is a hallmark of cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The response of the CF airway epithelium to the opportunistic pathogen Pseudomonas aeruginosa is characterized by altered inflammation and apoptosis. In this study, we examined innate immune recognition and epithelial responses at the level of the gap junction protein connexin43 (Cx43) in polarized human airway epithelial cells upon infection by PAO1. We report that PAO1 activates cell surface receptors to elicit an intracellular signaling cascade leading to enhancement of gap junctional communication. Expression of Cx43 involved an opposite regulation exerted by JNK and p38 MAPKs. PAO1-induced apoptosis was increased in the presence of a JNK inhibitor, but latter effect was prevented by lentiviral expression of a Cx43-specific short hairpin RNA. Moreover, we found that JNK activity was upregulated by pharmacological inhibition of CFTR in Calu-3 cells, whereas correction of a CF airway cell line (CF15 cells) by adenoviral expression of CFTR reduced the activation of this MAPK. Interestingly, CFTR inhibition in Calu-3 cells was associated with decreased Cx43 expression and reduced apoptosis. These results indicate that Cx43 expression is a component of the response of airway epithelial cells to innate immune activation by regulating the survival/apoptosis balance. Defective CFTR could alter this equilibrium with deleterious consequences on the CF epithelial response to P. aeruginosa. Copyright © 2014 by The American Association of Immunologists, Inc.

Published
2014

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