PUBLICATION
Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-Mediated Neutrophil Response
- Authors
- Le Moigne, V., Rodriguez Rincon, D., Glatigny, S., Dupont, C.M., Langevin, C., Ait Ali Said, A., Renshaw, S.A., Floto, R.A., Herrmann, J.L., Bernut, A.
- ID
- ZDB-PUB-220127-6
- Date
- 2022
- Source
- American journal of respiratory cell and molecular biology 66(4): 439-451 (Journal)
- Registered Authors
- Langevin, Christelle, Renshaw, Steve A.
- Keywords
- none
- MeSH Terms
-
- Animals
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Dual Oxidases
- Mice
- Mycobacterium Infections, Nontuberculous*/microbiology
- Neutrophils*
- Roscovitine/pharmacology
- Roscovitine/therapeutic use
- Zebrafish
- PubMed
- 35081328 Full text @ Am. J. Respir. Cell Mol. Biol.
Citation
Le Moigne, V., Rodriguez Rincon, D., Glatigny, S., Dupont, C.M., Langevin, C., Ait Ali Said, A., Renshaw, S.A., Floto, R.A., Herrmann, J.L., Bernut, A. (2022) Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-Mediated Neutrophil Response. American journal of respiratory cell and molecular biology. 66(4):439-451.
Abstract
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 bi-allelic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We therefore examined whether Roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defence, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immuno-pathophysiology, combined with murine and human approaches, we sought to determine the effects of Roscovitine on innate immune responses to tissue injury and pathogens in CF condition. We show that Roscovitine exerts anti-inflammatory and pro-resolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial ROS-mediated neutrophil trafficking, by reducing DUOX2/NADPH-oxidase activity, and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. Importantly, while 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, favouring 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 safety targeting inflammation in CF.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping