mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke

作者：Lingqi Kong, Wenyu Li, En Chang, Wuxuan Wang, Nan Shen, Xiang Xu, Xinyue Wang, Yan Zhang, Wen Sun, Wei Hu, Pengfei Xu, Xinfeng Liu · 发表于：Frontiers in Immunology · 年份：2022 · DOI：10.3389/fimmu.2022.860977 · 被引用次数：170 · 研究领域：interferon and immune responses、Neuroinflammation and Neurodegeneration Mechanisms、Immune Response and Inflammation

Neuroinflammation is initiated in response to ischemic stroke, and is usually characterized by microglial activation and polarization. Stimulator of interferon genes (STING) has been shown to play a critical role in anti-tumor immunity and inflammatory diseases. Nevertheless, the effect and underlying mechanisms of STING on microglial polarization after ischemic stroke remain unclarified. In this study, acute ischemic stroke was simulated using a model of middle cerebral artery occlusion (MCAO) at adult male C57BL/6 mice in vivo and the BV2 microglia oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro . The specific STING inhibitor C-176 was administered intraperitoneally at 30min after MCAO. We found that the expression of microglial STING was increased following MCAO and OGD/R. Pharmacologic inhibition of STING with C-176 reduced the ischemia/reperfusion (I/R)-induced brain infarction, edema and neuronal injury. Moreover, blockade of STING improved neurological performance and cognitive function and attenuated neuronal degeneration in the hippocampus after MCAO. Mechanistically, both in vivo and in vitro , we delineated that STING could promote the polarization of microglia towards the M1 phenotype and restrain M2 microglia polarization via downstream pathways, including interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). In addition, mitochondrial DNA (mtDNA), which is released to microglial cytoplasm induced by I/R injury, could facilitate micro...