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, morpholino-mediated 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.
Highlights
Than the cell cycle; in particular, it is involved in transcription of Mcl-1, an important neutrophil survival protein[15,16]
This could be achieved by strategies such as reducing the production of pro-inflammatory mediators, decreasing recruitment of inflammatory granulocytes or promoting the migration of granulocytic cells away from sites of wounding[26], or promoting local granulocyte apoptosis[27]
It is known that driving granulocyte apoptosis pharmacologically can resolve inflammation in experimental settings in vivo[3,12,13,28]
Summary
Than the cell cycle; in particular, it is involved in transcription of Mcl-1, an important neutrophil survival protein[15,16]. CDK inhibitor drugs enhance resolution of neutrophilic inflammation in mouse models in vivo[12,13] It is currently unknown whether CDK9 (and/or CDK7) inhibition in vivo is the target responsible for the neutrophil apoptosis-driving effect of these inhibitors, as mouse knockouts of CDK9 and its associated proteins are embryonically lethal[19]. We and others have previously shown that CDK inhibitor compounds can enhance inflammation resolution in zebrafish after tissue injury[21,22] It is not known whether these pro-resolution effects are dependent upon CDK9 inhibition in vivo. We show that knocking down La-related protein 7 (LaRP7, an endogenous negative regulator of the P-TEFb complex) has the opposite effect to knocking down CDK9, and promoted increased neutrophilic inflammation at the site of wounding. This study represents the first clear demonstration of the pro-resolution role of CDK9 inhibition in neutrophils in an in vivo model of inflammation and injury
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