星形胶质细胞IL-17A/Act1通路在老年小鼠术后认知功能障碍的作用及机制研究

Postoperative cognitive dysfuncsystem is a common complication after surgery. Astrocytes are critical in the development of inflammation of central nervous system. Our previous study has found that suppression of astrocytes activation could reduce the degree of central nervous system inflammation and decrease the incidence of POCD. Published study has reported that IL-17A bound to IL-17A receptors on astrocytes. Our data suggested that IL-17 antibody inhibited the activation of astrocytes, decreased the expression of Act1 protein and improved the postoperative cognition. In view of the fact that Act1 is an important target of inflammation, we hypothesize that surgical stress promote the secretion of IL-17, which activates the IL-17A/Act1 signaling pathway of astrocytes in the hippocampus, and eventually causes excessive inflammatory reaction and the incidence of POCD. This project aims to research the correlation between IL-17A and POCD in multilevel using a tibial fracture model in mice. We firstly study the role of astrocytes in POCD by inhibition of the activation of astrocytes using GFAPTK transgenic mice. In addition, we also hope to illustrate the impact of the activation of the IL-17A/Act1 signaling pathway of astrocytes in the central nervous system inflammation. We believe that the results of this project will provide valuable evidences for POCD prevention (POCD) caused by the inflammation of central nervous.

术后认知功能障碍（POCD）是术后神经系统主要并发症，与中枢炎症相关。星形胶质细胞在中枢炎症中起着重要作用。我们前期发现：抑制星形胶质细胞活化可通过降低老年小鼠中枢炎症反应遏制POCD的发生。IL-17A可与星形胶质细胞膜上IL-17RA结合。预实验发现在体应用IL-17抗体可抑制星形胶质细胞活化，降低Act1蛋白表达，并改善术后认知。鉴于Act1是炎症反正中重要调控靶点，我们推测：手术应激促进IL-17生成，并激活海马星形胶质细胞IL-17A/Act1信号通路引起细胞活化，导致过度炎症反应及POCD形成。本项目建立小鼠胫骨骨折POCD模型，多层次研究IL-17A与POCD相关性；采用药物GCV作用GFAPTK基因小鼠，抑制星形胶质细胞活化，首次在体反向揭示星形胶质细胞在POCD发生中作用；以期阐明星形胶质细胞IL-17/Act1通路在调控中枢炎症反应作用，为POCD防治策略提供实验依据。

术后认知功能障碍（POCD）是术后主要神经系统并发症，与中枢炎症相关。星形胶质细胞可直接受外周炎症和中枢炎症调控，但其在POCD形成中的作用不详。我们前期研究发现：抑制星形胶质细胞活化后可降低中枢炎症反应，减缓POCD的发生和严重程度。通过系列研究，我们证实外周麻醉手术的创伤可引发IL-17A的释放，流经血脑屏障后，IL-17A直接与星形胶质细胞膜上的IL-17RA结合，激活海马星形胶质细胞活化；采用抑制剂和慢病毒等干预方式，发现IL-17A通过Act1/NF-κB信号通路调控星形胶质细胞炎症因子和趋化因子等释放；不仅趋化外周血液中的单核细胞、巨噬细胞进入中枢，而且会促进这些细胞进入中枢以及激活中枢定居的小胶质细胞，向M1方向活化，产生更多的炎性细胞因子，以旁分泌方式再次作用星形胶质细胞，造成中枢炎症反应的持续放大，形成恶性循环，最终导致POCD的发生。.在本项目的探索下，观察到星形胶质细胞活化与炎症小体NLRP3密切相关，级联放大中枢炎症反应。并发现右美托咪定具有抑制胶质细胞炎症反应，具有治疗作用，为POCD的防治提供了新的思路和措施。研究成果发表于 Frontiers In Pharmacology(2021); 同时进一步发现NLRP3炎症小体的上游的基因调控机制，发现LncRNAs4344通过作用miRNA-138-5p调控NLRP3炎症，导致NLRP3相关炎症反应的激活，研究成果发表于经典期刊 Journal of Inflammation Research(2021); Brain Behavior and Immunity(2021)。同时，汇总了麻醉药物对星形胶质细胞在中枢神经炎症反应中的作用；阐述了星形胶质细胞中的线粒体动力学和应激能量代谢在老年退行性变疾病中的作用。系列成果发表高质量论文4篇。. . 系列的研究发现，证实IL-17A和NLRP3在介导POCD发生发展中起着重要作用，为POCD的防治提供了新思路。