Liu Qing, Zhang Man-Man, Guo Min-Xia, Zhang Qiu-Ping, Li Na-Zhi, Cheng Jie, Wang Shi-Le, Xu Guang-Hui, Li Cheng-Fu, Zhu Ji-Xiao, Yi Li-Tao
Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Fujian province, Xiamen, 361021, PR China.
Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Jiangxi province, Nanchang, 330004, PR China.
J Neuroimmune Pharmacol. 2022 Dec;17(3-4):503-514. doi: 10.1007/s11481-021-10037-0. Epub 2022 Jan 3.
Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1β signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1β signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1β expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.
重度抑郁症的特征是单胺神经递质、神经营养因子缺乏以及持续性神经炎症。小胶质细胞激活与神经炎症相关的精神疾病有关，伴有含NLR家族pyrin结构域3（NLRP3）炎性小体。在此，我们研究了其小分子抑制剂MCC950抑制NLRP3对慢性不可预测轻度应激（CUMS）诱导的炎症活性和抑郁样小鼠的影响，随后进行了包括蔗糖偏好试验和强迫游泳试验在内的行为测试。检测了前额叶皮质中NLRP3/半胱天冬酶-1/白细胞介素-1β信号通路和小胶质细胞形态。结果表明，CUMS导致蔗糖偏好降低和不动时间增加，而NLRP3抑制剂MCC950可逆转这些变化。此外，抑制NLRP3可减少小胶质细胞数量，并通过形态三维重建将小胶质细胞的激活状态转变为静息状态。此外，抑制NLRP3可使前额叶皮质中的NLRP3/半胱天冬酶-1/白细胞介素-1β信号通路失活。免疫荧光结果表明，MCC950处理后小胶质细胞中NLRP3和白细胞介素-1β表达降低。因此，抑制NLRP3也可降低促炎细胞因子水平。总之，本研究表明抑制小胶质细胞NLRP3可预防前额叶皮质应激诱导的神经炎症，并提示小胶质细胞NLRP3可能是抑郁症治疗的潜在靶点之一。
