Abstract
BackgroundReceptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD.MethodsWe assessedRIPK1expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patientsviaimmunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, usingRipk1S25D/S25Dkinase-deficient mice and the RIPK1 kinase inhibitor GSK′547.ResultsRIPK1expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increasedRipk1expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.ConclusionsRIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.
Funder
Vlaams Instituut voor Biotechnologie
Stichting Tegen Kanker
Concerted Research Action of Ghent University
CRIG and GIGG consortia
Fund for Scientific Research in Flanders
EOS
National Health and Medical Research Council
AstraZeneca
Publisher
European Respiratory Society (ERS)
Subject
Pulmonary and Respiratory Medicine
Cited by
15 articles.
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