S1P/mTOR轴介导小胶质细胞表型转化在脑白质缺血后髓鞘再生微环境中的作用

Cerebral small vessel disease with or without whiter matter ischemia (WMI) contributes to vascular cognitive impairment. The process of myelin loss is always accompanied with microgliosis after white matter ischemia. Microglia activation can induce microenvironment change of myelin regeneration, which is one of crucial factors for the differentiation, maturation and re-myelination of oligodendrocyte progenitor cells. Microenvironment change of myelin regeneration is highly dependent on microglial polarization and M2 microglia is beneficial to myelin repair. It has been reported that S1P/mTOR pathway makes an important role in the conversion of macrophage/microglia phenotype. In our preliminary study, we found that S1P/mTOR signaling pathway was up-regulated significantly and S1P receptor agonist FTY720 exerts neuroprotection after WMI. In the present study, we try to investigate the relationship between microglial M1/M2 phenotype and de/re-myelination after WMI, and elucidate the molecular mechanisms of microglia polarization transition induced by S1P/mTOR pathway. M2 microglia might provide a beneficial microenvironment for myelin regeneration and is helpful for tissue reconstruction and functional restoration, which might be a novel and potential method to treat vascular cognitive decline after WMI in the future.

脑小血管病和脑白质缺血(WMI)是血管性认知功能障碍的重要危险因素。WMI后髓鞘脱失是其重要的病理过程，往往伴随着小胶质细胞(MG)明显激活。MG介导的髓鞘再生微环境改变，是影响少突胶质前体细胞分化成熟并有效髓鞘化的重要因素。MG所处的不同表型与髓鞘再生微环境密切相关，M2型MG更有利于髓鞘修复。我们前期研究发现，S1P受体激动剂可以诱导体外MG向M2型转化，给予mTOR抑制剂可以部分逆转MG表型转化，提示S1P/mTOR通路在小胶质细胞M1/M2表型转化中起着重要的作用。本研究拟通过小胶质细胞消融、基因敲除、药物干预和双光子成像等技术手段，探讨MG及不同表型与WMI后髓鞘脱失/再生的关系，阐明S1P/mTOR调控MG表型转化的分子机制，改善脑白质缺血后受损髓鞘的再生微环境，促进MG和少突胶质细胞之间的稳态重构，加快机体的结构重建和功能恢复，为WMI后认知功能障碍的临床治疗提供新的思路。

脑小血管病和脑白质缺血(WMI)是血管性认知功能障碍的重要危险因素。WMI后髓鞘脱失是其重要的病理过程，往往伴随着小胶质细胞(MG)明显激活。MG介导的髓鞘再生微环境改变，是影响少突胶质前体细胞分化成熟并有效髓鞘化的重要因素。MG所处的不同表型与髓鞘再生微环境密切相关，M2型MG更有利于髓鞘修复。我们研究发现，S1P受体激动剂Fingolimod可以调控体外MG向M2型转化，给予mTOR抑制剂可以部分逆转MG表型转化，提示S1P/mTOR通路在小胶质细胞促炎/抗炎的表型转化中起着重要的作用；通过对小胶质细胞表型相关信号通路进行筛选发现，Fingolimod通过影响STAT3通路促进M1型小胶质细胞向M2型小胶质细胞转化；Fingolimod干预过的小胶质细胞上清液可以促进少突胶质细胞前体细胞的成熟和分化；在低灌注性脑白质缺血损伤状态下，Fingolimod改善脑白质缺血后受损髓鞘的再生微环境，促进模型小鼠的受损髓鞘的修复，改善认知功能。本研究探讨MG及不同表型与WMI后髓鞘脱失/再生的关系，阐明了S1P/mTOR调控MG表型转化的分子机制，促进MG和少突胶质细胞之间的稳态重构，加快机体的结构重建和功能恢复，为脑白质缺血后认知功能障碍的临床治疗提供了新的思路。