HMGB1调控小胶质细胞极化在血管性认知障碍小鼠OPCs成熟分化中的作用及机制研究

Vascular cognitive impairment (VCI) has high incidence and is lack of efficient therapy.White matter lesions caused by myelin damage are the most common pathological changes of VCI. Our previous work found that the increased polarization of pro-inflammatory (M1) microglia induced inflammatory reaction was an important reason for oligodendrocyte precursors (OPCs) failed to maturate and differentiate，and eventually resulted in myelin damage. High-mobility group box 1 (HMGB1), an important late-stage brain inflammatory factor, is closely related to microglial activation and depression. It was also found in our previous study that patients with depression showed high level of HMGB1 related to myelin damage. Therefore, we hypothesize that the regulation of HMGB1-related signaling pathway to inhibit M1 microglial polarization may promote the maturation of OPCs and remyelination. It may be an important target of VCI therapy. We propose an experiment on the expression of HMGB1 and the relationship with M1 type of microglia and demyelination with the model of microglia cell line, VCI mice and VCI patients. In this study we will regulate the HMGB1-related signaling pathway to inhibit M1 micrglial polarization for the maturation of OPCs and myelin regeneration, to attenuate cognitive disorder. The hypothesis above can provide an important theoretical basis and new targets for VCI treatment.

血管性认知障碍(Vascular Cognitive Impairment，VCI)发病率高，无有效疗法，主要病理改变为脑白质髓鞘损伤。我们发现小胶质细胞M1型极化的促炎反应是导致少突胶质前体细胞(Oligodendrocyte Precursor Cells, OPCs)成熟障碍致髓鞘损伤的重要原因。高迁移率族蛋白1 (High-mobility group box 1, HMGB1)是小胶质细胞激活相关的晚期炎性因子，前期研究患者血清HMGB1与髓鞘蛋白水平相关。因此，通过调节HMGB1信号通路来抑制M1型小胶质细胞极化，促进OPCs成熟可能成为VCI的治疗靶点。本课题将分别以细胞、VCI动物及患者为研究对象，观察HMGB1信号通路与OPCs及髓鞘损伤的关系，并通过调控HMGB1通路关键蛋白减少M1型小胶质细胞极化，促进OPCs成熟，修复髓鞘，改善认知，为VCI治疗提供新思路。

血管性认知障碍（Vascular cognitive impairment，VCI）是仅次于阿尔茨海默病的一类认知障碍，脑白质损伤是VCI重要的病理改变。我们前期研究发现脑缺血后小胶质细胞促炎极化致少突胶质前体细胞（Oligodendrocyte Precursor Cells, OPCs）成熟障碍是脑白质髓鞘损伤与修复失败的重要原因。高迁移率组蛋白1（High-mobility group box 1，HMGB1）是一种广泛存在的非组蛋白DNA结合蛋白，病理状态下可主动或被动方式释放至胞外，参与诱导免疫细胞激活并引起炎症反应。本课题针对HMGB1在VCI脑白质损伤中的作用和机制进行了研究。首先建立双侧颈动脉血流阻断的VCI小鼠模型，动物行为学出现认知损伤与抑郁样行为，脑切片显示成熟少突胶质细胞及髓鞘损伤，小胶质细胞激活，HMGB1表达升高，而通过HMGB1拮抗剂甘草酸对VCI小鼠进行处理后，VCI小鼠情绪认知损伤、小胶质细胞活化及少突胶质细胞和髓鞘损伤均得到改善，证明了HMGB1与VCI脑白质损伤的相关性。同时我们通过向健康小鼠侧脑室注射外源性HMGB1，也可造成小鼠情绪及认知功能损伤，脑切片观察到小胶质细胞活化、OPC成熟障碍及髓鞘损伤，证明了HMGB1可导致OPC成熟障碍与脑白质损伤。进一步通过动物和细胞实验证明了HMGB1是通过Src/NFκB通路导致小胶质细胞促炎极化。最后，在VCI患者外周血中检测到HMGB1含量较同龄健康对照组显著升高，HMGB1水平与认知障碍的程度无关。本研究从细胞、动物、患者三个层次，研究了HMGB1在血管性认知障碍OPC成熟障碍及髓鞘损伤中的作用，可能通过Src/NFκB通路致小胶质细胞促炎性极化发生作用。在本研究基础上，项目组成员获国家自然科学基金项目1项，发表SCI论文3篇，核心期刊5篇，培养研究生5名。