CB2R/PGC-1α通路调控脑缺血后小胶质细胞表型转化的作用及机制研究

Promoting the microglial phenotype transformation from detrimental M1 phenotype to beneficial M2 phenotype is believed to be a key in reducing neuroinflammation after cerebral ischemia. Mitochondrial biogenesis increases the number of mitochondria and improves mitochondrial function. A recent research showed that promoting microglial mitochondrial biogenesis significantly increased the expression of M2 microglial marker Arg-1, suggesting that mitochondrial biogenesis plays an important role in regulating the microglial phenotype. Thus, it is important to explore effective measures in regulating microglial mitochondrial biogenesis. In the central nervous system, cannabinoid receptor type 2 (CB2R) is mainly expressed on microglia, and whose activation transforms microglia from M1 phenotype to M2 phenotype. In addition, CB2R can regulate the activation of PGC-1α. Therefore, we hypothesize that CB2R-induced PGC-1α activation promotes microglial mitochondrial biogenesis, which can transform microglia from M1 phenotype to M2 phenotype, and thus alleviate the brain damage after ischemia. The aim of our study is to investigate the neuroprotective effect of CB2R/PGC-1α pathway in regulating microglial phenotype transformation from M1 phenotype to M2 phenotype by using the methods of molecular biology and RNA interference. This study will provide novel therapeutic targets for the treatment of ischemic stroke.

脑缺血后，促进小胶质细胞从有害的M1表型向有益的M2表型转化，是抑制神经炎性损伤的关键，但分子机制不清限制对小胶质细胞表型转化的调节。线粒体生物发生可增加其数量和质量，通过促进线粒体生物发生能够增加M2型小胶质细胞标志物Arg-1表达，提示小胶质细胞线粒体生物发生在调控其表型中发挥重要作用，需探索有效的干预途径。大麻素2型受体（CB2R）在中枢神经系统主要表达于小胶质细胞，其活化可促进M1型小胶质细胞向M2型转化，且能够激活线粒体生物发生关键转录因子PGC-1α。据此，我们提出如下假设：激活CB2R诱导PGC-1α活化促进线粒体生物发生，调控脑缺血后小胶质细胞从M1型向M2型转化，从而减轻脑缺血损伤。本研究将应用形态、功能和分子生物学等方法及RNA干扰等手段，阐明CB2R/PGC-1α通路在调控小胶质细胞从M1型向M2型转化诱导脑保护中的重要作用及机制，为治疗脑缺血损伤提供新的干预靶点。

脑缺血后，促进小胶质细胞从有害的M1表型向有益的M2表型转化，是抑制神经炎性损伤的关键，但分子机制不清限制对小胶质细胞表型转化的调节。线粒体生物发生可增加其数量和质量，通过促进线粒体生物发生能够增加M2型小胶质细胞标志物Arg-1表达，提示小胶质细胞线粒体生物发生在调控其表型中发挥重要作用，需探索有效的干预途径。大麻素2型受体（CB2R）在中枢神经系统主要表达于小胶质细胞，其活化可促进M1型小胶质细胞向M2型转化，且能够激活线粒体生物发生关键转录因子PGC-1α。.本项目选择离体原代神经元及原代小胶质细胞OGD和在体脑缺血（MCAO）模型，以PGC-1α为切入点，综合应用形态、功能和分子生物学等方法，寻找决定小胶质细胞表型的关键机制，探讨CB2R/PGC-1α通路在调控脑缺血后小胶质细胞表型转化中的重要作用。结果显示在脑缺血损伤后，激活大麻素CB2R可以通过上调PGC-1α调控小胶质细胞从M1表型向M2表型转化，发挥脑保护作用；也发现通过干预小胶质细胞线粒体生物发生水平可以调控小胶质细胞活化状态，证实线粒体生物发生是调节小胶质细胞功能的关键机制。.本研究明确了调控小胶质细胞表型的关键分子机制，也为防治神经炎症引起的继发性脑损伤提供新的可能干预靶点。申请人以第一或通讯作者将相关结果发表在Neuropharmacology和Cell Mol Neurobiol等杂志上。