Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 66, Issue 4, Pages 439-451Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2021-0406OC
Keywords
cystic fibrosis; roscovitine; neutrophil activity; DUOX2-NADPH oxidase; Mycobacterium abscessus
Funding
- European Community's Horizon 2020-Research and Innovation Framework Program (H2020-MSCA-IF-2016) under the Marie Curie Individual Fellowship CFZEBRA [751977]
- Fondation pour la Recherche Medicale -Espoirs de la Recherche-Program [ARF201909009156]
- United Kingdom Cystic Fibrosis (CF) Trust Strategic Research Centre award [SRC002]
- Wellcome Trust [107032AIA, GR077544AIA]
- Medical Research Council [MR/M004864/1, G0700091]
- United Kingdom CF Trust workshop funding [160161]
- United Kingdom CF Trust Strategic Research Centre award [SRC018]
- antimicrobial resistance cross-council - Medical Research Council [MRNO2995X/1]
- Medical Research Council [MR/M004864/1, G0700091] Funding Source: researchfish
- Marie Curie Actions (MSCA) [751977] Funding Source: Marie Curie Actions (MSCA)
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The study found that roscovitine has anti-inflammatory and pro-resolution effects in zebrafish, reducing neutrophil trafficking by targeting DUOX2/NADPH oxidase activity, accelerating inflammation resolution, and inducing neutrophil apoptosis and reverse migration. However, despite enhancing bacterial killing in human CF macrophages, roscovitine led to more severe infection in mouse and zebrafish models by compromising granuloma formation.
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.
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