HV1调控小胶质细胞自噬介导的神经炎症在慢性脑缺血白质损伤中的作用机制

Cerebral small vessel diseases characterized by white matter ischemic damage (WMI) contributes to vascular cognitive impairment. The neuropathologic process of myelin loss is always accompanied with activation of microglia (MG) and ROS production after white matter ischemia. Immunologic process mediated by microglia activation control microenvironment state 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 functional subpopulation of microglia, in which M2 subtype is beneficial to myelin repair. In our preliminary study, we found that microglial HV1 channel was activated with up-regulation of ROS production, and HV1 KO could switch MG polarization toward M2 type after ischemic stroke. It has been reported that ROS is associated with autophagy process, which plays an important role in the conversion of microglia/macrophage phenotype. In the present study, we try to investigate the relationship between MG phenotype and myelin loss after WMI, and elucidate the potentially molecular mechanisms of HV1-mediated MG autophagy in MG phenotype. 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.

脑白质缺血(WMI)是脑小血管病及血管性认知功能障碍的主要病理过程，核心特征是少突胶质细胞凋亡和髓鞘脱失，伴随小胶质细胞(MG)活化及大量活性氧簇(ROS)和炎症因子的产生。不同表型MG介导的炎症免疫微环境是影响受损髓鞘修复的重要因素，M2型MG更有利于再髓鞘化过程。我们前期研究发现，MG特异性质子通道HV1可直接促使ROS产生，调控MG表型转化而影响脑缺血后神经修复；文献报道，ROS与自噬过程关系密切。据此推测，WMI后MG上HV1通道被激活并释放ROS，导致MG自噬失衡，M1/M2表型向促炎状态倾斜，介导慢性脑缺血白质损伤后的脱髓鞘病理过程。本研究拟通过MG消融、基因敲除等手段，探讨MG不同表型与WMI后髓鞘脱失/再生的关系，阐明HV1调控MG自噬过程及神经炎症的分子机制，改善WMI后受损髓鞘的再生微环境，促进MG和少突胶质的内稳态重构，为WMI后认知功能障碍的临床治疗提供新的思路。

脑白质缺血(WMI)是脑小血管病及血管性认知功能障碍的主要病理过程，核心特征是少突胶质细胞凋亡和髓鞘脱失，伴随小胶质细胞(MG)活化及大量活性氧簇(ROS)和炎症因子的产生。不同表型MG介导的炎症免疫微环境是影响受损髓鞘修复的重要因素，M2型MG更有利于再髓鞘化过程。我们研究发现，MG特异性质子通道HV1可直接促使ROS产生，调控MG表型转化而影响脑缺血后神经修复；WMI后MG上HV1通道被激活并释放ROS，导致MG自噬失衡，M1/M2表型向促炎状态倾斜，介导慢性脑缺血白质损伤后的脱髓鞘病理过程。. 我们另外还发现，脑白质受损后髓鞘明显脱失，小胶质细胞显著活化，脂质吞噬超载聚集引起自噬-溶酶体加工受损可能导致脂质进一步积累，形成恶性循环；脂质积聚的小胶质细胞显示出吞噬、自噬-溶酶体和炎性因子分泌等功能障碍。我们首次证实，阶段性而非持续性抑制小胶质细胞自噬-溶酶体的过度激活，可以发挥更好的髓鞘碎片降解作用。我们通过多组学联合分析进一步阐明，阶段性抑制自噬后小胶质细胞的脂质代谢增强，尤其是共轭亚油酸途径的激活，通过PPAR-γ通路减轻神经炎症、恢复小胶质细胞促再生特性和髓鞘修复、改善空间学习功能。因此，我们提出针对小胶质细胞自噬-溶酶体过度激活或补充共轭亚油酸的措施、减轻获得性脂质过载引起的溶酶体功能障碍、促进有序的脂质代谢、改善慢性神经炎症可能是脑白质损伤的潜在治疗策略。在本项目的支持下，相关成果发表在PNAS，Signal Transduct Target Ther、Journal of Neuroinflammation、Frontiers in Immunology等国际学术期刊。

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