Study on the role and mechanism of S100A8/A9 regulating TLR4 signaling pathway in white matter injury after subarachnoid hemorrhage

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.