Sirt1-ROS-TRAF6 Signaling-Induced Pyroptosis Contributes to Early Injury in Ischemic Mice

作     者：Weijie Yan Wei Sun Jiahui Fan Haiqing Wang Song Han Junfa Li Yanling Yin Weiiie Yan;Wei Sun;Jiahui Fan;Haiqing Wang;Song Han;Junfa Li;Yanling Yin

作者机构：Department of NeurobiologyMinistry of Education Key Laboratory for Neurodegenerative DisordersCapital Medical UniversityBeijing 100069China Department of NeurologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086China 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2020年第36卷第8期

页      面：845-859页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (31771292 and 31571162)。 

主　　题：ROS Stroke Pyroptosis TRAF6 Sirt1 

摘      要：Stroke is an acute cerebro-vascular disease with high incidence and poor prognosis,most commonly ischemic in nature.In recent years,increasing attention has been paid to inflammatory reactions as symptoms of a stroke.However,the role of inflammation in stroke and its underlying mechanisms require exploration.In this study,we evaluated the inflammatory reactions induced by acute ischemia and found that pyroptosis occurred after acute ischemia both in vivo and in vitro,as determined by interleukin-1β,apoptosis-associated speck-like protein,and caspase-1.The early inflammation resulted in irreversible ischemic injury,indicating that it deserves thorough investigation.Meanwhile,acute ischemia decreased the Sirtuin 1(Sirtl)protein levels,and increased the TRAF6(TNF receptor associated factor 6)protein and reactive oxygen species(ROS)levels.In further exploration,both Sirtl suppression and TRAF6 activation were found to contribute to this pyroptosis.Reduced Sirtl levels were responsible for the production of ROS and increased TRAF6 protein levels after ischemic exposure.Moreover,N-acetyl-L-cysteine,an ROS scavenger,suppressed the TRAF6 accumulation induced by oxygen-glucose deprivation via suppression of ROS bursts.These phenomena indicate that Sirtl is upstream of ROS,and ROS bursts result in increased TRAF6 levels.Further,the activation of Sirtl during the period of ischemia reduced ischemiainduced injury after 72 h of reperfusion in mice with middle cerebral artery occlusion.In sum,these results indicate that pyroptosis-dependent machinery contributes to the neural injury during acute ischemia via the Sirt1-ROS-TRAF6 signaling pathway.We propose that inflammatory reactions occur soon after oxidative stress and are detrimental to neuronal survival;this provides a promising therapeutic target against ischemic injuries such as a stroke.