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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.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0406oc","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T17:04:02Z","timestamp":1643216642000},"page":"439-451","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":11,"title":["Roscovitine Worsens\n                    <i>Mycobacterium abscessus<\/i>\n                    Infection by Reducing DUOX2-mediated Neutrophil Response"],"prefix":"10.1093","volume":"66","author":[{"given":"Vincent","family":"Le Moigne","sequence":"first","affiliation":[{"name":"Infection et Inflammation, Inserm\/UVSQ, UMR 1173, Universit\u00e9 Paris-Saclay, Montigny-le-Bretonneux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Rodriguez Rincon","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Glatigny","sequence":"additional","affiliation":[{"name":"Infection et Inflammation, Inserm\/UVSQ, UMR 1173, Universit\u00e9 Paris-Saclay, Montigny-le-Bretonneux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M.","family":"Dupont","sequence":"additional","affiliation":[{"name":"Institut de Recherche en Infectiologie de Montpellier, Centre National de la Recherche Scientifique, UMR 9004, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Langevin","sequence":"additional","affiliation":[{"name":"Inrae, Infectiologie Exp\u00e9rimentale des Rongeurs et des Poissons, UE 0907, Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amel","family":"Ait Ali Said","sequence":"additional","affiliation":[{"name":"Infection et Inflammation, Inserm\/UVSQ, UMR 1173, Universit\u00e9 Paris-Saclay, Montigny-le-Bretonneux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Renshaw","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Cardiovascular Disease, Sheffield Medical School, and"},{"name":"Firth Court, Bateson Centre, University of Sheffield, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Andres","family":"Floto","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, United Kingdom"},{"name":"Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Infection et Inflammation, Inserm\/UVSQ, UMR 1173, Universit\u00e9 Paris-Saclay, Montigny-le-Bretonneux, France"},{"name":"H\u00f4pital Raymond Poincar\u00e9, AP-HP, Groupe Hospitalo-universitaire Paris-Saclay, Garches, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1928-8329","authenticated-orcid":false,"given":"Audrey","family":"Bernut","sequence":"additional","affiliation":[{"name":"Infection et Inflammation, Inserm\/UVSQ, UMR 1173, Universit\u00e9 Paris-Saclay, Montigny-le-Bretonneux, France"},{"name":"Department 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