自噬介导小胶质细胞代谢重编程参与慢性低灌注脑白质损伤的机制研究

慢性低灌注脑白质损伤(WMI)是血管性认知功能障碍的重要原因，核心病理特征是髓鞘脱失和小胶质细胞(MG)活化。不同表型MG介导的炎症微环境是影响受损髓鞘修复的重要因素。我们前期研究发现，WMI后活化的MG内聚集大量自噬小体，调控自噬可维持MG的抗炎状态，更有利于髓鞘修复。细胞代谢组学的初步结果也提示，MG活化后细胞内糖脂代谢旺盛，抑制自噬信号可诱导MG代谢重编程，并导致亚油酸等脂质蓄积。据此推测，WMI后MG自噬失衡，启动以糖酵解为主的能量代谢，活化并维持MG的慢性炎症状态，参与介导脑白质脱髓鞘的病理过程；抑制MG自噬后，出现由糖酵解转向脂质代谢的重编程现象，调控MG表型由不利于髓鞘修复的促炎型向抗炎型转化。本研究拟通过MG消融、基因敲除、调控代谢等手段，阐明MG代谢重编程参与WMI后神经炎症的分子机制，以改善受损髓鞘的再生微环境，重建神经单元的内稳态，为WMI后认知障碍提供新的治疗思路。

Cerebral small vessel disease, manifested as white matter ischemia (WMI), is very common clinically. The core pathological features are demyelination, followed by activation of microglia (MG). 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 anti- inflammatory (M2) subtype is beneficial to myelin repair. In our previous reports, the aggregation of autophagic bodies was found in activated microglia after WMI and the regulation of MG autophagy can maintain the anti-inflammatory state of MG, which is more beneficial to myelin repair. Our preliminary results of microglial metabonomics also suggested that in the state of MG activation and inhibition of autophagy, metabolic reprogramming occurred, intracellular glycolipid metabolism was exuberant, and linoleic acid and other lipids accumulated. It is speculated that the autophagy imbalance of MG after WMI initiates glycolysis-based metabolic reprogramming, then activates and maintains the chronic inflammatory state of MG, finally mediates the pathological process of demyelination; however, when inhibiting the process of autophagy, the metabolic level of microglia changes from glycolysis to lipid metabolism. It mediates the transformation of MG phenotype from pro-inflammatory type to anti-inflammatory type. The purpose of this study is to clarify the molecular mechanism of metabolic reprogramming mediated by MG autophagy in neuroinflammation after WMI. Several methods, including MG ablation, gene knockout and metabolic reprogramming, will be used in our study. M2 microglia modulated by cellular metabolic reprogramming 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.