NLRP3炎症小体调控海马小胶质细胞表型转化参与抑郁症的机制研究

Depression is a common mental disorder and has now been recognized to have an overall impact on global illness, for which current treatments are inadequate and confront with some dilemma, owing to the pathogenesis of depression is not well understood. These is accumulating evidence for psychological, as well as physical stressors can activate immune and inflammation processes and lead to increased cytokine levels, contributing to the development of depression. There have been several excellent reviews of this work, but the current opinion presents a novel aspect of the immune-inflammation process in the response to stress and depression: that interkeukin-1 beta?(IL-1beta?) and its regulator, ''the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome'', are a bridge between psychological stress and depression, which correlates with microglia activation in brain based on some observations (histopathology and PET scans). However, the molecular mechanism has not been clarified. In the project, using specific inhibitors and molecular imaging integrating with a quantitative spatiotemporal analysis of microglia morphology, we observe in vivo and in vitro the effects of NLRP3 inflammasome-IL-1beta on the activation of hippocampal microglia activation and M1/M2 phenotype switch in different murine depression models and primary cell co-culture system, verify their role in regulating adult hippocampal neurogenesis and demonstrate the effects of this regulation pattern on altering depression-like behavior or anti-depressive treatment. Related to this project is the possibility that the NLRP3 inflammasome represents a potential sensor for stress and provides a possible pathway between stress and depression, suggesting novel strategies for treating depression.

抑郁症是一个突出的全球性精神神经性疾病，临床治疗存在的诸多问题均归因于其发病机理尚未完全明确。目前抑郁症的神经免疫研究已被视为最具潜力的新进展。细胞因子IL-1beta及其调控蛋白NLRP3炎症小体作为应激所致中枢免疫炎症反应的核心，与中枢免疫效应细胞-小胶质细胞激活密切相关，但其参与抑郁症的机制仍不清楚。本研究拟采用定量时空形态学分析结合活体分子影像学、特异性抑制剂、RNA干扰等技术，从体内与体外两个层面，观察抑郁动物模型形成不同阶段或抗抑郁治疗前后NLRP3炎症小体-IL-1beta通路对海马小胶质细胞激活及表型转化的影响，阐明其内在调控机制及对海马神经发生的调节效应，并进一步明确这种调控模式对动物抑郁样行为或抗抑郁治疗的影响，为深入了解抑郁症发病机制、明确NLRP3炎症小体作为潜在抗抑郁靶点的可行性、为寻求新的更加有效的抗抑郁治疗方案提供科学依据。

抑郁症的高发病率和严重的经济负担及现有抗抑郁药副作用大、复发率高等问题使得加强抑郁症的防治、寻找新的抗抑郁靶点具有重要意义。细胞因子IL-1beta及其调控蛋白NLRP3炎症小体作为应激所致中枢免疫炎症反应的核心，与中枢免疫效应细胞-小胶质细胞激活密切相关，但其参与抑郁症的机制仍不清楚。本项目在两种慢性应激所致的大鼠和小鼠抑郁症模型（CMS和CUS抑郁模型）及LPS所致的急性抑郁小鼠模型上，观察到海马脑区小胶质细胞的激活、炎性因子的改变及NLRP3炎性小体各组分在mRNA和蛋白水平的变化；给予抗抑郁药氯丙咪嗪治疗后，以上这些因素都随之改善；同时通过原代小胶质细胞培养和BV2小胶质细胞系体外实验，进一步验证上述实验结果。此外，引入NLRP3-/-小鼠和ASC-/-小鼠以制备慢性或急性抑郁模型，与野生型小鼠相比，KO小鼠不显示抑郁样行为及神经炎性的改变。该研究结果表明海马小胶质细胞-NLRP3炎性小体可能参与了抑郁症的形成及氯丙咪嗪的抗抑郁治疗作用。IL-1beta-NLRP3炎性小体与海马神经发生及小胶质细胞的表型转化的相互关系尚需进一步的研究阐明。但是，本项目的研究结果对于阐明海马小胶质细胞NLRP3炎性小体在抑郁症及抗抑郁治疗中的作用具有重要的理论意义，为开发新的抗抑郁药提供新的思路或借鉴。