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1. A mouse model of MSU-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1β as relevant therapy for gout patients

Author

Mariotte, Alexandre, De Cauwer, Aurore, Po, Chrystelle, Abou-Faycal, Chérine, Pichot, Angélique, Paul, Nicodème, Aouadi, Ismael, Carapito, Raphael, Frisch, Benoit, Macquin, Cécile, Chatelus, Emmanuel, Sibilia, Jean, Armspach, Jean-Paul, Bahram, Seiamak, and Georgel, Philippe

Subjects
Inflammation, Mice, Knockout, Imiquimod, Gout, Administration, Topical, Injections, Subcutaneous, Interleukin-1beta, Magnetic Resonance Imaging, Antioxidants, Uric Acid, Disease Models, Animal, Mice, Adjuvants, Immunologic, Acute Disease, Animals, Cytokines, Research Paper
Abstract

Rationale: The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1β in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1β secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Methods: Acute urate crystal inflammation was obtained by subcutaneous injections of MSU crystals in mice. Symptoms were followed by scoring, cytokine quantification by ELISA and western blot, gene expression by RT-qPCR and RNAseq; Magnetic Resonance Imaging was also used to assess inflammation. Results: We provide an extensive clinical, biological and molecular characterization of an acute uratic inflammation mouse model which accurately mimics human gout. We report the efficacy of topical imiquimod treatment and its impact on Interferon-dependent down modulation of Il-1β gene expression in this experimental model. Conclusion: Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities for gout patients.

Published
2020

2. NLRP3- and AIM2-autonomy in a mouse model of MSU crystal-induced acute inflammation in vivo highlights imiquimod-dependent targeting of Il-1E expression as relevant therapy for gout patients

Author

Mariotte, Alexandre, De Cauwer, Aurore, Po, Chrystelle, Abou-Fayçal, Cherine, Pichot, Angélique, Paul, Nicodème, Aouadi, Ismael, Carapito, Raphael, Frisch, Benoit, Macquin, Cécile, Chatelus, Emmanuel, Sibilia, Jean, Armspach, Jean-Paul, Bahram, Seiamak, Georgel, Philippe, Frisch, Benoit, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Equipe 2 - Bases Moléculaires de la Progression des Cancers du Poumon, Inserm U823, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Plate-forme GENOMAX (Inserm U1109), Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA)-Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Rhumatologie, Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Rhumatologie, CHU Strasbourg, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ICube Laboratory, University of Strasbourg, CNRS, France, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

L'article est publié dans la revue sous le titre définitif :"A mouse model of MSU-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1β as relevant therapy for gout patients"; International audience; The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1 in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1 secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Here, we provide an extensive clinical, biological and molecular characterization of the acute uratic inflammation mouse model induced by subcutaneous injection of MSU crystals, which accurately mimics human gout. Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities, among which the use of topical application of imiquimod to promote interferon-dependent anti-inflammatory action maybe relevant. All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Published
2020

3. Gut Dysbiosis during Influenza Contributes to Pulmonary Pneumococcal Superinfection through Altered Short-Chain Fatty Acid Production

Author

Sencio, Valentin, Barthelemy, Adeline, Tavares, Luciana, Machado, Marina, Soulard, Daphnée, Cuinat, Céline, Queiroz-Junior, Celso Martins, Noordine, Marie-Louise, Salomé-Desnoulez, Sophie, Deryuter, Lucie, Foligné, Benoit, Wahl, Céline, FRISCH, Benoit, Vieira, Angelica, Paget, Christophe, Milligan, Graeme, Ulven, Trond, Wolowczuk, Isabelle, Faveeuw, Christelle, Le Goffic, Ronan, Thomas, Muriel, Ferreira, Stéphanie, Teixeira, Mauro, Trottein, François, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Instituto de Ciencias Biologicas [Minas Gerais], Universidade Federal de Minas Gerais [Belo Horizonte] (UFMG), Université Paris-Saclay, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lille Inflammation Research International Center (LIRIC), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Genoscreen [Lille], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire de chimie bioorganique (LCB), Centre National de la Recherche Scientifique (CNRS), Centre for Translational Pharmacology [Glasgow, Scotland, UK] (Institute of Molecular, Cell and Systems Biology), University of Glasgow, Department of Pharmacology [Copenhagen, Denmark], University of Copenhagen = Københavns Universitet (KU), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), This work was supported in part by INSERM, CNRS, University of Lille, Pasteur Institute of Lille, re´ gion des Hauts-de-France, state of Minais Gerais/FAPEMIG (Franco-Brazilian call 2014-2015, FLUMICROBIOT, to F.T. and M.T.), Innovation Fund Denmark (grant 0603-00452B to T.U.), the Biotechnology and Biosciences Research Council (grant BB/S000453/1 to G.M.), and Agence Nationale de la Recherche (grant ANR-17-CE15-0020-01, ACROBAT, to F.T.). V.S. and A.B. received salary support (PhD fellowship) from Lille University and the Fondation pour la Recherche Me´ dicale (V.S.), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Copenhagen = Københavns Universitet (UCPH), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-17-CE15-0020,ACROBAT,Rôle de l'axe poumon/intestin/moelle osseuse et du microbiote au cours de la grippe(2017), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, CHU Lille, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Université de Strasbourg (UNISTRA), Innovation Fund Denmark: grant 0603-00452, UK Research & Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC): BB/S000453/1, Lille University, Fondation pour la Recherche Médicale, Région des Hauts-de-France, INSERM, CNRS, State of Minais Gerais/FAPEMIG (Franco-Brazilian call 2014-2015, FLUMICROBIOT), TROTTEIN, François, and Rôle de l'axe poumon/intestin/moelle osseuse et du microbiote au cours de la grippe - - ACROBAT2017 - ANR-17-CE15-0020 - AAPG2017 - VALID

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], food restriction, Acetates, digestive system, Pneumococcal Infections, Receptors, G-Protein-Coupled, Influenza, Human, Macrophages, Alveolar, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Animals, Humans, influenza A virus, Lung, Respiratory Tract Infections, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, gut microbiota, bacterial superinfection, virus diseases, Feeding Behavior, free fatty acid receptor 2, Fatty Acids, Volatile, Gastrointestinal Microbiome, macrophages, Gastrointestinal Tract, Mice, Inbred C57BL, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, lcsh:Biology (General), microbial dysbiosis, Superinfection, Dysbiosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, acetate, short-chain fatty acid
Abstract

Summary: Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection. : Sencio et al. provide insights into the mechanisms that underlie bacterial superinfection post-influenza. The authors demonstrate that influenza infection remotely alters the production of short-chain fatty acids (SCFAs) by the gut microbiota. Supplementation with acetate or pharmacological activation of the SCFA receptor FFAR2 reduces susceptibility to secondary bacterial infection. Keywords: influenza A virus, bacterial superinfection, gut microbiota, microbial dysbiosis, food restriction, short-chain fatty acid, acetate, free fatty acid receptor 2, macrophages

Published
2020
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4. How Polydopamine Modulates Biological Responses to PTFE Prostheses

Author

Talon, Isabelle, Schneider, Anne, Mathieu, Eric, Senger, Bernard, Frisch, Benoit, Seguin, Cendrine, Ball, Vincent, Hemmerlé, Joseph, Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie pédiatrique [CHU Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Frisch, Benoit, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Biomaterials, congenital, hereditary, and neonatal diseases and abnormalities, Polydopamine, [CHIM.MATE] Chemical Sciences/Material chemistry, [CHIM.POLY] Chemical Sciences/Polymers, [CHIM.POLY]Chemical Sciences/Polymers, Expanded Polytetrafluoroethylene, health services administration, health care facilities, manpower, and services, education, Electron Microscopy, [CHIM.MATE]Chemical Sciences/Material chemistry, Functionalization
Abstract

International audience; Diaphragm repair after congenital diaphragmatic hernia is associated with hernia recurrence due to prosthesis failure. Expanded polytetrafluoroethylene (e-PTFE), a synthetic non-degradable biomaterial, is currently used for those diaphragmatic defect repairs. The drawback of e-PTFE is its poor wettability that leads to coating difficulties, bonding that could favor implant integration. However, polydopa-mine (PDA) can be deposited as well on organic as on inorganic substrates. Therefore, we assessed the biological responses of a clinically used e-PTFE bio-material treated with PDA in two different manners: one impregnated with PDA and the other coated with a one side PDA film. Mechanical properties of the raw e-PTFE, the PDA soaked biomaterial and the PDA coated surface were characterized by colloidal probe atomic force microscopy. Behaviors of primary human fibroblasts and Wharton's jelly stem cells were investigated by electron micro-scopy. Findings reveal that the mechanical properties at the microscopic scale are not modified by the PDA treatments. Cells spread onto both PDA functionalized substrates. In addition, microscopic observations disclose numerous focal cell contacts, evidencing cell attachment, and cytoplasmic projections particularly with the nanoscale PDA coating. Results clearly suggest that PDA in general but above all the PDA coating enhance cellular colonization of the implant material.

Published
2019
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5. A mouse model of MSU-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1 beta as relevant therapy for gout patients

Author

Mariotte, Alexandre, de Cauwer, Aurore, Po, Chrystelle, Abou-Faycal, Cherine, Pichot, Angelique, Paul, Nicodème, Aouadi, Ismaïl, Carapito, Raphael, Frisch, Benoit, Macquin, Cecile, Chatelus, Emmanuel, Sibilia, Jean, Armspach, Jean-Paul, Bahram, Seiamak, Georgel, Philippe, univOAK, Archive ouverte, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie des Systèmes Fonctionnels, and Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire
Abstract

Rationale : The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1β in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1β secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Methods : Acute urate crystal inflammation was obtained by subcutaneous injections of MSU crystals in mice. Symptoms were followed by scoring, cytokine quantification by ELISA and western blot, gene expression by RT-qPCR and RNAseq; Magnetic Resonance Imaging was also used to assess inflammation. Results : We provide an extensive clinical, biological and molecular characterization of an acute uratic inflammation mouse model which accurately mimics human gout. We report the efficacy of topical imiquimod treatment and its impact on Interferon-dependent down modulation of Il-1β gene expression in this experimental model. Conclusion : Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities for gout patients.

Published
2020
Full Text
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6. Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection\ud through altered short-chain fatty acid production

Author

Sencio, Valentin, Barthelemy, Adeline, Tavares, Luciana P., Machado, Marina Gomes, Soulard, Daphnée, Cuinat, Céline, Queiroz-Junior, Celso Martins, Noordine, Marie Louise, Salomé-Desnoulez, Sophie, Deryuter, Lucie, Foligné, Benoit, Wahl, Céline, Frisch, Benoit, Vieira, Angelica Thomaz, Paget, Christophe, Milligan, Graeme, Ulven, Trond, Wolowczuk, Isabelle, Faveeuw, Christelle, Le Goffic, Ronan, Thomas, Muriel, Ferreira, Stéphanie, Teixeira, Mauro M., and Trottein, François

Subjects
digestive system
Abstract

Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection.

Published
2020

7. Evaluation of the anti-tumor effect of PLK1-specific siRNA delivery using a nanosystem containing pyridylthiourea- polyethylenimine

Author

Robinet, Eric, Meyer, F, Gossart, JB, Pascal, E, Calligaro, Cynthia, Heuillard, E, Goncalvez, M, Wu, Tao, Baumert, Thomas, Pessaux, Patrick, Kichler, Antoine, Frisch, Benoit, Zuber, Guy, univOAK, Archive ouverte, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie des Systèmes Fonctionnels, Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2015

8. Fluorocarbon-peptide conjugates (FPC): new concept to increase the metabolic stability of peptides for therapeutic applications

Author

M. Ramanoudjame, Sridevi, Esteoulle, Lucie, Flahault, Adrien, Seguin, Cendrine, Riché, Stéphanie, Heurtault, Béatrice, Hany, Romain, Gizzi, Patrick, Iturrioz, Xavier, Fournel, Sylvie, Frisch, Benoît, Llorens-Cortes, Catherine, Bonnet, And Dominique, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Frisch, Benoit

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2018

9. Exogenous Activation of Invariant Natural Killer T Cells by α-Galactosylceramide Reduces Pneumococcal Outgrowth and Dissemination Postinfluenza

Author

Christelle Faveeuw, Christophe Paget, Adeline Barthelemy, François Trottein, Josette Fontaine, Maya Hassane, Benoît Frisch, Béatrice Heurtault, Stoyan Ivanov, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Libanaise, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Frisch, Benoit

Subjects
0301 basic medicine, Time Factors, 030106 microbiology, Galactosylceramides, Biology, medicine.disease_cause, Lymphocyte Activation, Microbiology, Virus, Pneumococcal Infections, 03 medical and health sciences, Mice, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Orthomyxoviridae Infections, Virology, medicine, Influenza A virus, Animals, Administration, Intranasal, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Natural killer T cell, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QR1-502, 3. Good health, Vaccination, Pneumococcal infections, Pneumonia, Disease Models, Animal, 030104 developmental biology, Treatment Outcome, Immunology, Pneumococcal pneumonia, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Natural Killer T-Cells, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Cell activation, Research Article
Abstract

Influenza A virus infection can predispose to potentially devastating secondary bacterial infections. Invariant natural killer T (iNKT) cells are unconventional, lipid-reactive T lymphocytes that exert potent immunostimulatory functions. Using a mouse model of postinfluenza invasive secondary pneumococcal infection, we sought to establish whether α-galactosylceramide (α-GalCer [a potent iNKT cell agonist that is currently in clinical development]) could limit bacterial superinfection. Our results highlighted the presence of a critical time window during which α-GalCer treatment can trigger iNKT cell activation and influence resistance to postinfluenza secondary pneumococcal infection. Intranasal treatment with α-GalCer during the acute phase (on day 7) of influenza virus H3N2 and H1N1 infection failed to activate (gamma interferon [IFN-γ] and interleukin-17A [IL-17A]) iNKT cells; this effect was associated with a strongly reduced number of conventional CD103+ dendritic cells in the respiratory tract. In contrast, α-GalCer treatment during the early phase (on day 4) or during the resolution phase (day 14) of influenza was associated with lower pneumococcal outgrowth and dissemination. Less intense viral-bacterial pneumonia and a lower morbidity rate were observed in superinfected mice treated with both α-GalCer (day 14) and the corticosteroid dexamethasone. Our results open the way to alternative (nonantiviral/nonantibiotic) iNKT-cell-based approaches for limiting postinfluenza secondary bacterial infections., IMPORTANCE Despite the application of vaccination programs and antiviral drugs, influenza A virus (IAV) infection is responsible for widespread morbidity and mortality (500,000 deaths/year). Influenza infections can also result in sporadic pandemics that can be devastating: the 1918 pandemic led to the death of 50 million people. Severe bacterial infections are commonly associated with influenza and are significant contributors to the excess morbidity and mortality of influenza. Today’s treatments of secondary bacterial (pneumococcal) infections are still not effective enough, and antibiotic resistance is a major issue. Hence, there is an urgent need for novel therapies. In the present study, we set out to evaluate the efficacy of α-galactosylceramide (α-GalCer)—a potent agonist of invariant NKT cells that is currently in clinical development—in a mouse model of postinfluenza, highly invasive pneumococcal pneumonia. Our data indicate that treatment with α-GalCer reduces susceptibility to superinfections and, when combined with the corticosteroid dexamethasone, reduces viral-bacterial pneumonia.

Published
2016
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