VSIG4通过抑制mtROS释放在巨噬细胞M1极化及脑出血炎症损伤中的机制研究

课题组前期研究表明：ICH后血肿周围组织巨噬细胞VSIG4表达增加；VSIG4-/-小鼠ICH后促进巨噬细胞M1极化，血肿吸收能力下降，神经功能缺损加重；VSIG4过表达抑制ICH后巨噬细胞M1极化，促进血肿吸收及神经损伤修复。结合线粒体能量代谢调控巨噬细胞极化的理论基础，进一步证实VSIG4可以降低mtROS释放从而抑制巨噬细胞M1极化。由此推测VSIG4通过活化PI3K-Akt-STAT3信号轴上调PDK2表达，促进PDH活性并抑制mtROS释放，进而负调巨噬细胞M1极化。本实验拟在ICH模型上，运用流式、WB、基因突变等技术，通过调控VSIG4表达，分析巨噬细胞M1/M2极化、神经炎症并探索具体的细胞代谢信号通路。本研究将从全新的角度阐明ICH炎症损伤的机制，深入探讨“VSIG4-线粒体-细胞极化”的作用模式，为ICH后细胞能量代谢调控巨噬细胞M1/M2极化提供理论依据和治疗靶点。

Our previous studies showed that:The expression of VSIG4 in the macrophages around the hematoma increased; VSIG4-/- promoted the polarization of macrophage M1, decreased the absorption capacity of hematoma, and aggravated the neurological deficit; The overexpression of VSIG4 could inhibit the polarization of macrophage M1 after intracerebral hemorrhage, and promoted the absorption of hematoma and neurological damage repair. Based on the theory that mitochondrial energy metabolism may regulate macrophage polarization, we further confirmed that VSIG4 can reduce mitochondrial mtROS release and inhibit macrophage M1 polarization.Therefore, We speculated that VSIG4 upregulated PDK2 expression by activating PI3K-Akt-STAT3 signal axis, promoted PDH activity and inhibited mtROS release, and further negatively regulated M1 polarization of macrophages. In this experiment, flow cytometry, Western Blot, chromatin immunoprecipitation and gene mutation were used to detect the expression of key enzymes such as PDH, regulate the expression of VSIG4, analyze the polarization of macrophage M1/M2 and neuroinflammation, and explore the specific cellular metabolic signal pathway. This study will clarify the mechanism of inflammatory injury in intracerebral hemorrhage from a new perspective, and further explore the mode of action of VSIG4-mitochondria-cell polarization, and provide theoretical basis and therapeutic target for cell energy metabolism to regulate M1 / M2 polarization of macrophages after intracerebral hemorrhage.