S100A8/A9调控TLR4信号通路在蛛网膜下腔出血后白质损伤中的作用及机制研究

White matter injury (WMI) has recently been reported to be associated with the motor deficit and cognitive dysfunction of subarachnoid hemorrhage (SAH) patients. A substantial body of evidence has established that microglia could dynamically change their phenotype after acute brain injury, termed to the M1 for pro-inflammation and M2 for anti-inflammation. The M1 phenotypic shift may propel WMI progression and represents a rational target for acute brain injury treatment. We previously demonstrated that modulation of the Toll like receptor 4 (TLR4) signaling pathway could consequently influence the microglia-related inflammatory response, thereby reduce white matter edema after SAH. Based on high-throughput sequencing, we recently found that the expression of S100A8/A9, as well as microglia phenotypic genes, were significantly changed after SAH. Notably, the S100A8/A9 complex is a new endogenous ligand of TLR4, which plays an important role in intracellular inflammatory signal transduction. Thus, we hypothesize that S100A8/A9 could modulate microglial phenotype via TLR4 signaling pathway, thereby affect WMI after SAH. To confirm our hypothesis, the following experiments are designed: 1. To evaluate the role of S100A8/A9 and TLR4 genes on microglial phenotype and WMI in mouse SAH model. 2. To investigate the specific mechanisms of S100A8/A9/TLR4 pathway on microglial phenotype mediated inflammatory response to oligodendrocytes myelination, as well as the direct interaction between S100A8/A9 and TLR4 in the primary cell culture model. This project is the continuation of our previous work that related to neuroinflammation after SAH. The specific mechanisms of microglia mediated WMI will be revealed to develop new therapeutic targets and provide scientific data for further clinical application.

白质损伤（WMI）与蛛网膜下腔出血（SAH）患者神经功能预后密切相关。小胶质细胞表型的差异直接决定WMI的不同走向。我们前期证实，抑制Toll样受体4（TLR4）炎症通路可改善SAH后白质水肿，基因测序发现小鼠SAH后脑中S100A8/A9及小胶质细胞表型相关基因表达明显上升。S100A8/A9是TLR4内源性配体，参与调控免疫细胞内炎症信号转导等过程。据此我们推测，S100A8/A9/TLR4信号通路在SAH后WMI中发挥重要作用。本研究拟在明确S100A8/A9及TLR4与SAH后小胶质细胞表型及WMI关系的基础上，进一步通过离体细胞培养模型，从表面标志物表达、炎症因子的释放等多角度阐释S100A8/A9通过TLR4调控小胶质细胞表型对髓鞘的影响。本研究是前期工作的延续，不仅可进一步揭示SAH后炎症反应介导WMI的关键机制，且为将来寻找有效治疗靶点、提高科研成果转化及临床应用奠定基础。

白质损伤（WMI）与蛛网膜下腔出血（SAH）患者神经功能预后密切相关。Toll样受体4（TLR4）介导小胶质细胞表型改变直接加重SAH后WMI。本研究通过高通量测序、神经影像等技术发现TLR4配体S100A8/A9参与调控SAH后神经炎症反应；TLR4基因缺失可调节小胶质细胞表型，进而减轻SAH小鼠白质损伤。我们通过体外实验进一步明确了S100A8/A9/TLR4信号通路在SAH后白质损伤中的作用及机制。本课题是前期研究的深入和拓展，课题核心发现有望为将来寻找有效治疗靶点、提高科研成果转化及临床应用奠定基础。