Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-mediated Neutrophil Response
| Autor: | Vincent Le Moigne, Daniela Rodriguez Rincon, Simon Glatigny, Christian M. Dupont, Christelle Langevin, Amel Ait Ali Said, Stephen A. Renshaw, R. Andres Floto, Jean-Louis Herrmann, Audrey Bernut |
|---|---|
| Přispěvatelé: | Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Cambridge [UK] (CAM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Plateforme d'Infectiologie Expérimentale des Rongeurs et Poissons (IERP (UE 0907)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Sheffield [Sheffield], Hôpital Raymond Poincaré [AP-HP], 160161, SRC018, G0700091, GR077544AIA, SRC002, 751977, H2020-MSCA-IF-2016, ARF201909009156, Wellcome Trust, WT: 107032AIA, MR/M004864/1, Medical Research Council, MRC: MRNO2995X/1, These authors contributed equally to this work. ‡These authors contributed equally to this work. §Present address: Laboratory of Pathogen Host Interactions, CNRS/UM, University of Montpellier, UMR 5235, Montpellier, France. Supported by the European Community’s Horizon 2020-Research and Innovation Framework Program (H2020-MSCA-IF-2016) under the Marie Curie Individual Fellowship CFZEBRA (751977) and by the Fondation pour la Recherche Médicale -Espoirs de la Recherche-Program (ARF201909009156) to A.B., a United Kingdom Cystic Fibrosis (CF) Trust Strategic Research Centre award (SRC002) and the Wellcome Trust (107032AIA) to R.A.F. and D.R.R., a Medical Research Council Programme grant (MR/M004864/1) to S.A.R., and United Kingdom CF Trust workshop funding (160161) and a United Kingdom CF Trust Strategic Research Centre award (SRC018) to A.B., S.A.R., and R.A.F. This work was supported by antimicrobial resistance cross-council funding from the Medical Research Council to the SHIELD consortium (MRNO2995X/1) to A.B. and S.A.R. The authors thank the CYMAGES and the Wolfson Light Microscopy (Medical Research Council grant G0700091) and Wellcome Trust (grant GR077544AIA) facilities. |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pulmonary and Respiratory Medicine
Mycobacterium abscessus Neutrophils Clinical Biochemistry neutrophil activity Cystic Fibrosis Transmembrane Conductance Regulator Mycobacterium Infections Nontuberculous Cell Biology [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract Dual Oxidases cystic fibrosis Mice Roscovitine Animals Molecular Biology DUOX2-NADPH oxidase Zebrafish Original Research |
| Zdroj: | Am J Respir Cell Mol Biol American Journal of Respiratory Cell and Molecular Biology American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, 2022, 66 (4), pp.439-451. ⟨10.1165/rcmb.2021-0406OC⟩ |
| ISSN: | 1044-1549 1535-4989 |
| Popis: | International audience; Persistent neutrophilic inflammation associated with chronic pulmonary infection causes progressive lung injury and, eventually, death in individuals with cystic fibrosis (CF), a genetic disease caused by biallelic mutations in the CF transmembrane conductance regulator (CFTR) gene. Therefore, we examined whether roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defense, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immunopathophysiology, combined with murine and human approaches, we sought to determine the effects of roscovitine on innate immune responses to tissue injury and pathogens in the CF condition. We show that roscovitine exerts antiinflammatory and proresolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial reactive oxygen species (ROS)-mediated neutrophil trafficking by reducing DUOX2/NADPH-oxidase activity and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. It is important to note that, although roscovitine efficiently enhances intracellular bacterial killing of Mycobacterium abscessus in human CF macrophages ex vivo, we found that treatment with roscovitine results in worse infection in mouse and zebrafish models. By interfering with DUOX2/ NADPH oxidase-dependent ROS production, roscovitine reduces the number of neutrophils at infection sites and, consequently, compromises granuloma formation and maintenance, favoring extracellular multiplication of M. abscessus and more severe infection. Our findings bring important new understanding of the immune-targeted action of roscovitine and have significant therapeutic implications for safely targeting inflammation in CF. Copyright |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|