Journal Article

Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-mediated Neutrophil Response

Ait Ali Said, Amel, Bernut, Audrey, Rodriguez Rincon, Daniela, Floto, R. Andres, Renshaw, Stephen A., Le Moigne, Vincent, Dupont, Christian M., Herrmann, Jean-Louis, Langevin, Christelle, Glatigny, Simon

2022

Overview

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 in human CF macrophages , 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 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.

• Publisher: American Thoracic Society
• Subject: Amputation / Animal models / Animals / Apoptosis / Chronic infection / Chronic obstructive pulmonary disease / Cyclin-dependent kinase / Cystic fibrosis / Cystic Fibrosis Transmembrane Conductance Regulator - genetics / Danio rerio / Dual Oxidases / Enzyme inhibitors / Genetic disorders / Granuloma / Human health and pathology / Immune response / Immune system / Inflammation / Innate immunity / Leukocyte migration / Leukocytes (neutrophilic) / Life Sciences / Macrophages / Mice / Mycobacterium abscessus / Mycobacterium Infections, Nontuberculous - microbiology / NAD(P)H oxidase / Neutrophils / Original Research / Pathogens / Pulmonology and respiratory tract / Reactive oxygen species / Roscovitine / Roscovitine - pharmacology / Roscovitine - therapeutic use / Zebrafish