人类τ蛋白聚集可通过升高T细胞内抗原1促进神经炎症  

Accumulation of human tau protein promotes neuroinflammation via increasing T-cell intracellular antigen 1

作　　者：刘侃玲 张瑶 LIU Kan-ling;ZHANG Yao(Center for Cardiovascular Clinical Medicine,Affiliated Liyuan Hospital,Tongji Medical College of HUST,Wuhan 430077,China;Department of Endocrinology,Affiliated Liyuan Hospital,Tongji Medical College of HUST,Wuhan 430077,China)

机构地区：[1]华中科技大学同济医学院附属梨园医院心血管临床医学中心,湖北武汉430077 [2]华中科技大学同济医学院附属梨园医院内分泌科,湖北武汉430077

出　　处：《中国病理生理杂志》2022年第7期1153-1160,共8页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金重大研究计划(No:9194920041);湖北省自然科学基金资助项目(No:2021CFB337)。

摘　　要：目的:探讨人类τ蛋白(human tau protein,hTau)聚集促进神经炎症的分子机制。方法:在C57小鼠海马组织过表达hTau以及小鼠神经母细胞瘤细胞株N2a转染hTau质粒后,通过Western blot、免疫荧光、免疫组化及RNA免疫沉淀等技术,检测炎症因子、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路、MAPK磷酸酶1(MAPK phosphatase 1,MKP1)及T细胞内抗原1(T-cell intracellular antigen 1,TIA1)等相关因子的表达变化。结果:过表达hTau上调促炎因子和TIA1蛋白水平,下调MKP1蛋白水平并激活MAPK通路。用小干扰RNA敲减TIA1可抑制hTau聚集诱导的MKP1蛋白水平下降和MAPK通路的激活;过表达TIA1则恢复hTau诱导的MKP1蛋白水平下调、MAPK通路激活和炎症因子水平上升。进一步研究发现,TIA1通过结合MKP1 mRNA而降低MKP1 mRNA水平,导致其蛋白水平下降。结论:hTau聚集通过上调TIA1抑制MKP1表达,诱导MAPK通路激活并促进下游炎症因子产生和释放,从而导致神经炎症的发生,促进τ蛋白病的发生和发展。AIM:Transcriptome analysis reveals that transgenic mice overexpressing human tau protein(hTau)have a significant proinflammatory response in the early stage of the disease,suggesting that hTau promotes the development of neuroinflammation,but the mechanism has not been clearly studied.METHODS:The AAV-hTau viruses were injected into the hippocampus of C57 mice. In vitro hTau plasmid was transfected into mouse neuroblastoma cell line N2a. Four weeks after AAV-hTau virus injection or 48 h after hTau plasmid transfection,the neuroinflammation-related factors were examined by Western blot,immunofluorescence,immunohistochemistry and RNA immunoprecipitation.RESULTS:Overexpression of hTau promoted the expression of proinflammatory factors,inhibited mitogen-activated protein kinase phosphatase 1(MKP1)and activated mitogen-activated protein kinase(MAPK)signaling pathway. Knockdown of T-cell intracellular antigen 1(TIA1)by small interfering RNA blocked the down-regulation of MKP1 and up-regulation of MAPK signaling pathway induced by hTau,while overexpression of TIA1 reversed these alternations. Further investigation revealed that TIA1 bound to MKP1 mRNA and inhibited its mRNA expression,leading to decline of its protein expression.CONCLUSION:hTau inhibits the expression of MKP1 via promoting the up-regulation of TIA1,leading to activation of MAPK signaling pathway and production of proinflammatory factors,which ultimately contributes to neuroinflammation and progress of tauopathies.

关 键 词：Τ蛋白 丝裂原活化蛋白激酶 丝裂原活化蛋白激酶磷酸酶1 T细胞内抗原1 神经炎症 

分 类 号：R741.02[医药卫生—神经病学与精神病学] R363.2[医药卫生—临床医学]