NLRP3炎症小体-IDO1-犬尿氨酸信号调控海马小胶质细胞活化参与抑郁症形成的机制研究及其治疗价值

Major depressive disorder (MDD), a common but serious mood disorder, may cause harmful health behaviors, increased morbidity and mortality, lost work productivity and augmented health care utilization. The difficulties of antidepressants treatment stem from its complex causes and unclear pathogenesis. The etiology of neural-immune-inflammation mechanism may be a breakthrough to improve the treatment of the plight. Our previous study already found that NLRP3 inflammasome-IDO1-kynurenine (KYN) signaling was significantly correlated with microglial activation in the hippocampus of depression model animals, but the underlying mechanism is still not clear. This project intends to use Quantitative and Temporal Morphological Analysis combined with live molecular imaging, specific inhibitors, RNA interference and knockout mice to observe the changes of NLRP3-IDO1-KYN signals during the process of depression and antidepressants treatment. To elucidate the specific molecular mechanism of NLRP3-IDO1-KYN signal and its metabolites in hippocampal microglia how to affect the function of neurons and cell death, we further explore the exploratory research of targeting NLRP3-IDO1-KYN signaling in the treatment of depression. It is bound to provide a new research perspective for the development of antidepressants treatment windows for depression and to provide theoretical and experimental evidence for seeking new and more effective treatment options.

抑郁症药物治疗困境源于其病因复杂、发病机制不详；明确抑郁症的共性特征-神经免疫炎症机理-可能是改善其治疗困境的突破口。我们前期发现抑郁症模型动物中NLRP3炎症小体-IDO1-犬尿氨酸（KYN）信号与海马脑区小胶质细胞活化存在重要相关性，然而其内在机制并不清楚。本项目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 干扰等技术结合基因敲除动物，观察抑郁形成过程中NLRP3-IDO1-KYN信号的变化规律及其对抗抑郁治疗的影响，阐明海马小胶质细胞内NLRP3调控IDO1-KYN信号及其代谢产物、影响神经元功能及细胞死亡的具体分子机制，并进一步进行靶向NLRP3-IDO1-KYN信号治疗抑郁症的探索性研究，必将为拓展抑郁症治疗药物窗口提供新的研究视角，为寻求新型更加有效治疗方案提供理论及实验依据。

抑郁症已经日益成为当代最突出的精神类疾病和主要的疾病负担。小胶质细胞是应激所致神经免疫反应的核心，NLRP3-IDO1-犬尿酸信号通路在神经免疫调节中发挥重要作用，但其参与抑郁症的机制仍不清楚。.本课题组采用Nlrp3-/-小鼠，结合慢性不可预知性温和应激所致的小鼠抑郁症模型（CUMS模型），LPS所致的急性抑郁小鼠模型以及肥胖，青光眼共病抑郁模型，取得以下成果和发现：利用LPS急性抑郁小鼠模型，发现NLRP3炎症小体及其下游核心炎症因子IL-1β是介导抑郁样行为的关键环节；利用磁共振成像（MRI）技术和IDO抑制剂1-MT，明确了NLRP3调控的IDO信号通路参与LPS介导的急性抑郁样行为，而临床抗抑郁用药氯丙咪嗪可能通过上述途径发挥抗抑郁药效并增加抑郁小鼠的海马体积；通过中药抗抑郁药理研究，我们阐明单体梓醇通过氧化应激介导的NLRP3炎性小体通路和神经炎症对慢性不可预知应激（CUMS）抑郁模型小鼠发挥良好的抗抑郁药效；此外，两项针对抑郁共病的研究发现NMDA诱导的视神经损伤及8周高脂饮食均可观察到小鼠存在显著的抑郁样表型，我们的结果表明NLRP3-IDO-犬尿酸信号通路及NLRP3调控的小胶质细胞活化可能是上述表型的发病机制。.以上结果揭示了NLRP3-IDO-犬尿酸信号通路调控小鼠抑郁样行为的重要作用和神经免疫机制，拓展并阐明了临床常用药氯丙咪嗪的抗抑郁药效的作用新机制，为开发靶向NLRP3-IDO1-犬尿酸通路的抑郁症药物及治疗方法提供了理论依据和实验证据。