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 (Sirt1) protein levels, and increased the TRAF6 (TNF receptor associated factor 6) protein and reactive oxygen species (ROS) levels. In further exploration, both Sirt1 suppression and TRAF6 activation were found to contribute to this pyroptosis. Reduced Sirt1 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 Sirt1 is upstream of ROS, and ROS bursts result in increased TRAF6 levels. Further, the activation of Sirt1 during the period of ischemia reduced ischemia-induced 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.

中文翻译：

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Sirt1-ROS-TRAF6 信号传导诱导的细胞焦亡有助于缺血小鼠的早期损伤。


脑卒中是一种发病率高、预后差的急性脑血管疾病，最常见的是缺血性脑卒中。近年来，作为中风症状的炎症反应受到越来越多的关注。然而，炎症在中风中的作用及其潜在机制需要探索。在本研究中，我们评估了急性缺血引起的炎症反应，发现通过白细胞介素-1β、凋亡相关斑点样蛋白和caspase-1测定，急性缺血后在体内和体外均发生细胞焦亡。早期炎症导致不可逆的缺血性损伤，表明值得彻底研究。同时，急性缺血降低了 Sirtuin 1 (Sirt1) 蛋白水平，并增加了 TRAF6（TNF 受体相关因子 6）蛋白和活性氧 (ROS) 水平。在进一步的探索中，发现 Sirt1 抑制和 TRAF6 激活都会导致这种细胞焦亡。 Sirt1 水平降低导致 ROS 产生，缺血暴露后 TRAF6 蛋白水平增加。此外，ROS 清除剂 N-乙酰-L-半胱氨酸通过抑制 ROS 爆发来抑制缺氧葡萄糖诱导的 TRAF6 积累。这些现象表明 Sirt1 是 ROS 的上游，ROS 爆发导致 TRAF6 水平增加。此外，在大脑中动脉闭塞的小鼠中，缺血期间Sirt1的激活减少了再灌注72小时后缺血引起的损伤。总之，这些结果表明焦亡依赖性机制通过Sirt1-ROS-TRAF6 信号通路导致急性缺血期间的神经损伤。 我们认为，氧化应激后不久就会发生炎症反应，并且不利于神经元的存活；这为预防中风等缺血性损伤提供了一个有前景的治疗靶点。