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Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

Research output: Contribution to journalArticle

Original languageEnglish
Article number36980
JournalScientific Reports
Early online date11 Nov 2016
DOIs
Publication statusE-pub ahead of print - 11 Nov 2016

Abstract

Neutrophilic inflammation is tightly regulated, and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro, and promote resolution of inflammation in rodent models. Here, we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholinomediated
knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation
resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation.

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