CysLTR1信号在脑损伤后小胶质细胞M2表型转化过程中促进神经再生的作用机制研究

Microglia are the most important inflammatory cells in the central nervous system, and play a key role in cell clearance, structural remodeling and inflammatory factor release after injury. However, it is still not clear how microglia regulate nerve regeneration after acute central nervous system injury. Identifying key regulatory factors is helpful to promote the regeneration and functional reconstruction of the injured area. The selective M2 activation of microglia may contribute to tissue repair, but the key mechanisms are unclear. Previous studies showed that the mechanism of inducing CysLT1R expression and selective M2 activation of microglia are identical. Inhibiting the STAT3 phosphorylation of microglia can induce leukotrienes production, a CysLT1R ligand, activate CysLT1R signaling, and promote nerve regeneration. Therefore, we will take this as the key point to elucidate a new mechanism that transformation of microglia M2 phenotype can induce leukotrienes production, activate CysLTR1 signaling pathway and achieve regeneration by inhibiting STAT3 signaling pathway after brain injury using cytology and animal experiments. We further hope to find out the key regulation factors and new theory for achieving activation of microglia phenotype of M2 to regulate nerve regeneration and repair after brain injury based on the epigenetic modification, to help alleviate nerve injury dysfunction.

小胶质细胞是中枢神经系统最重要的炎症反应细胞。然而，急性中枢神经系统损伤后小胶质细胞如何调控神经再生目前仍悬而未决，寻找关键性的调控因素将有助于促进损伤区神经再生和功能重建。小胶质细胞选择性的M2型激活可有助于组织修复，然而关键机制不清。以往研究发现诱导CysLT1R表达的机制与调控小胶质细胞选择性M2激活的机制是一致的，并且小胶质细胞STAT3磷酸化的抑制可以诱导CysLT1R配体白三烯的生成，激活CysLT1R信号，促进神经再生。因此，我们将以此为重点，通过细胞与小鼠皮层控制损伤模型动物实验，深入阐明颅脑损伤后，小胶质细胞M2表型的转化通过抑制STAT3信号通路增加半胱氨酰白三烯的表达，从而激活干细胞CysLTR1信号通路实现神经再生的新机制，寻找出关键性的调控因素并提出基于表观遗传修饰以实现激活小胶质细胞M2表型转化调控损伤后神经再生和修复的新理论，以帮助减轻神经损伤后的功能障碍。

小胶质细胞是中枢神经系统最重要的炎症反应细胞。然而，急性中枢神经系统损伤后小胶质细胞如何调控神经再生目前仍悬而未决，寻找关键性的调控因素将有助于促进损伤区神经再生和功能重建。小胶质细胞选择性的M2型激活可有助于组织修复，然而关键机制不清。本项目首先通过细胞与动物性实验，发现M2型小胶质细胞可以诱导小鼠SVZ区细胞增殖，STAT3敲减后小胶质细胞的CysLTR1表达显著高于未敲减组，提示抑制STAT3信号可以激活小胶质细胞的CysLTR1信号。明确了小胶质细胞M2表型转化可以通过抑制STAT3 信号通路增加半胱氨酰白三烯的表达，从而激活干细胞CysLTR1信号通路实现神经再生。另外，我们通过细胞与动物学实验，明确了激活PPAR-γ信号通路，可以实现将小胶质细胞诱导为M2型小胶质细胞，从而具备抗炎和吞噬功能，抑制了相关炎症反应的发生和相关炎症因子的表达。同时，PPAR-γ可通过抑制mTOR信号通路抑制相关炎症因子的表达和相关炎症的发生。通过本项目研究的实施，我们寻找出关键性的调控因素并提出基于表观遗传修饰以实现激活小胶质细胞M2表型转化调控损伤后神经再生和修复的新理论，以帮助减轻神经损伤后的功能障碍。