Dexmedetomidine preconditioning alleviated murine liver ischemia and reperfusion injury by promoting macrophage M2 activation via PPARγ/STAT3 signaling

Abstract

BackgroundAlthough a protective role of dexmedetomidine in liver ischemia and reperfusion (IR) injury has been reported, the underlying mechanism remains to be determined. The aim of this study is to analyze the effects of dexmedetomidine on the regulation of macrophage innate immune activation during liver IR. MethodsMice were randomly divided into dexmedetomidine preconditioning (DEX) and phosphate buffered saline vehicle control (VEH) groups. A murine 70% warm liver IR model was used, and liver injury and intrahepatic inflammation was compared between groups. Bone marrow-derived macrophages (BMDMs) were stimulated with LPS in the presence or absence of dexmedetomidine. The inflammatory cytokine production was measured, and the macrophage M1/M2 polarization was determined in different groups. The underlying mechanism of dexmedetomidine in regulating macrophage M2 activation was also analyzed. ResultsCompared to mice observed in the control group, mice in the DEX group showed reduced liver injury and diminished proinflammatory immune responses in livers post IR. In vitro, dexmedetomidine pretreatment promoted BMDMs M2 activation, as evidenced by increased Arg1 and Mrc1 gene induction, decreased iNOS gene induction, inhibited phosphorated-signal transducer and activator of transcription 1 (p-STAT1) but enhanced p-STAT6 expression, much lower levels of proinflammatory TNF-α and IL-6, and higher levels of anti-inflammatory IL-10 cytokine secretion. Signaling pathway analysis revealed that peroxisome proliferator-activated receptor-γ (PPARγ)/ STAT3 activation was upregulated in BMDMs with dexmedetomidine pretreatment. Furthermore, PPARγ knockdown by siRNA not only inhibited STAT3 activation but also abrogated the promotion effects of macrophage M2 activation in BMDMs pretreated with dexmedetomidine. Finally, in vivo PPARγ inhibition in macrophages by siRNA significantly increased liver IR injury and intrahepatic inflammation in mice from the Dex group, with no significant effect in the VEH group. ConclusionsOur results indicate that dexmedetomidine preconditioning inhibited intrahepatic proinflammatory innate immune activation by promoting macrophage M2 activation in a PPARγ/STAT3 dependent manner. Our results demonstrate a novel innate immune regulatory mechanism by dexmedetomidine preconditioning during liver IR injury.