β-arrestin 2 调控小胶质细胞免疫表型保护单纯疱疹病毒性脑炎的机制研究

Microglial M1/M2 phenotype plays an important role in various nervous system diseases. The key molecules and related signaling pathways in the regulation of microglial phenotype in herpes simplex encephalitis (HSE) are undefined. Toll-like receptors (TLRs) are key factors involved in initiating an innate immune response and regulating the immune cell phenotype. β-arrestin 2 (Arrb2) plays a crucial role in TLR signaling through multi-target intervention. Our preliminary data have shown that Arrb2 expression was decreased after herpes simplex virus infection, and the survival rate was significantly higher in Arrb2 overexpression transgenic mice than that in wild-type mice. Also, Arrb2 overexpression decreased M1 type proinflammatory cytokines and increased M2 type anti-inflammatory cytokines expression. We hypothesize that Arrb2 might restrain inflammation in HSE brain by regulating the TLR signaling pathway and modifying the immune phenotype of microglia. We will employ laboratory techniques including gene transfection, EMSA, coimmunoprecipitation, and flow cytometry in vivo and in vitro experiment. We intend to assess whether Arrb2 could inhibit microglial activation and clarify the molecular mechanism of neuroprotection in HSE models, providing a new method for clinical treatment of HSE.

小胶质细胞活化后的免疫表型(M1/M2)在神经系统疾病中起重要作用，单纯疱疹病毒性脑炎(HSE)中调控小胶质细胞免疫表型的关键分子及相关信号通路尚不清楚。Toll样受体(TLRs)是先天性免疫细胞免疫信号启动及免疫表型调控的关键因子，β-arrestin 2(Arrb2)可通过多靶点干预对TLR信号通路发挥调节作用。我们前期研究发现：单纯疱疹病毒感染后，小胶质细胞内Arrb2表达降低；Arrb2高表达转基因小鼠生存率显著高于野生型小鼠，脑组织中M1型促炎因子表达减少，M2型抗炎因子增多。据此我们推测，Arrb2可通过干预TLR信号通路调控小胶质细胞免疫表型，抑制HSE脑组织神经炎症反应。本课题拟通过建立HSE细胞模型和动物模型，采用基因转染、EMSA、免疫共沉淀、流式细胞术等技术，探讨Arrb2调控小胶质细胞免疫反应的功能，明确其保护HSE神经细胞的分子机制，为临床治疗HSE提供新的思路。

小胶质细胞活化后的免疫表型(M1/M2)在神经系统疾病中起重要作用，单纯疱疹病毒性脑炎(HSE)中调控小胶质细胞免疫表型的关键分子及相关信号通路尚不清楚。Toll样受体(TLRs)是先天性免疫细胞免疫信号启动及免疫表型调控的关键因子，β-arrestin 2(Arrb2)可通过多靶点干预对TLR信号通路发挥调节作用。本课题通过建立HSE细胞模型和动物模型，采用基因转染、EMSA、免疫共沉淀、流式细胞术等技术，探讨Arrb2调控小胶质细胞免疫反应的功能，明确其保护HSE神经细胞的分子机制。我们研究发现：单纯疱疹病毒感染后，小胶质细胞内Arrb2表达降低；Arrb2高表达转基因小鼠生存率显著高于野生型小鼠，脑组织中M1型促炎因子表达减少，M2型抗炎因子增多。进一步研究发现Arrb2可通过干预TLR信号通路调控小胶质细胞免疫表型，抑制HSE脑组织神经炎症反应，保护血脑屏障并减少神经细胞的凋亡，可以为临床治疗HSE提供新的干预靶点。