阿尔茨海默病易感基因TREM2抑制小胶质细胞NLRP3炎症小体活性减轻神经炎症反应的机制研究  

Alzheimer’s Disease Susceptibility Gene TREM2 Ameliorates Neuroinflammation by Inhibition of Microglial NLRP3 Inflammasome Activation

作　　者：韦斌 蒋腾[1] 练慧文 段瑞 付欣欣 张颖冬[1] WEI Bin;JIANG Teng;LIAN Hui-wen;DUAN Rui;FU Xin-xin;ZHANG Ying-dong(Department of Neurology,Nanjing First Hospital,Nanjing Medical University,Nanjing 210006,China;The First School of Clinical Medicine,Nanjing Medical University,Nanjing 210029,China)

机构地区：[1]南京医科大学附属南京医院(南京市第一医院)神经内科,南京210006 [2]南京医科大学第一临床医学院,南京210029

出　　处：《中国临床神经科学》2022年第5期487-492,共6页Chinese Journal of Clinical Neurosciences

基　　金：国家自然科学基金面上项目(编号:81974156);国家科技部科技创新2030-“脑科学与类脑研究”重大项目(编号:2021ZD020180)。

摘　　要：目的明确2型髓样细胞触发受体(TREM2)抑制小胶质细胞介导的神经炎症反应的生物学机制。方法①将人HMC3小胶质细胞与Aβ_(1-42)(5μmol·L^(-1))共培养24 h(Aβ_(1-42)刺激组);②使用慢病毒介导的基因调控技术对HMC3小胶质细胞的TREM2进行沉默及过表达,再与Aβ_(1-42)(5μmol·L^(-1))共培养24 h(分别为TREM2沉默慢病毒组和TREM2过表达慢病毒组);上述干预方式均另设置相应对照组(对照沉默慢病毒组和对照过表达慢病毒组)和空白对照组(不加任何溶剂及对照慢病毒)。对上述HMC3小胶质细胞用Western blot法检测TREM2蛋白和NLRP3蛋白水平,ELISA法观察促炎介质IL-1β和IL-18浓度。结果①Aβ_(1-42)刺激组:HMC3小胶质细胞TREM2表达水平在Aβ_(1-42)刺激下逐渐升高(P<0.05);Aβ_(1-42)刺激可上调NLRP3蛋白水平(P<0.05),使IL-1β和IL-18浓度升高(P<0.05)。②TREM2沉默慢病毒组:沉默TREM2表达可上调NLRP3蛋白水平(P<0.05),并升高IL-1β和IL-18浓度(均P<0.05)。③TREM2过表达慢病毒组:过表达TREM2可显著下调NLRP3蛋白水平(P<0.05),并降低IL-1β和IL-18浓度(均P<0.05)。结论TREM2可通过抑制小胶质细胞NLRP3炎症小体活性减轻神经炎症反应。Aim To investigate the underlying mechanism by which triggering receptor expressed on myeloid cells 2(TREM2)inhibits microglia-mediated neuroinflammation.Methods Human HMC3 microglial cells were stimulated with Aβ_(1-42)(5μmol·L^(-1))for 24 h.Next,a lentivirus-mediated strategy was employed to manipulate TREM2 expression in HMC3 microglial cells.At 24 h after Aβ_(1-42)(5μmol·L^(-1))stimulation,NLRP3 protein levels in HMC3 microglial cells were evaluated by Western blot,and the concentrations of IL-1βand IL-18 in culture medium were assessed by ELISA.Results Aβ_(1-42)(5μmol·L^(-1))stimulation significantly increased TREM2 protein levels in HMC3 microglial cells.Meanwhile,the protein levels of NLRP3 in HMC3 microglial cells and the concentrations of IL-1βand IL-18 in culture medium were markedly elevated after Aβ_(1-42)(5μmol·L^(-1))stimulation.The increments of NLRP3 protein levels as well as IL-1βand IL-18 concentrations were further elevated by TREM2 knockdown and were attenuated by TREM2 overexpression.Conclusion TREM2 could ameliorate neuroinflammation by inhibition of microglial NLRP3 inflammasome activation.

关 键 词：阿尔茨海默病 2型髓样细胞触发受体 小胶质细胞 NLRP3炎症小体 神经炎症 

分 类 号：R741[医药卫生—神经病学与精神病学]