A Critical Role for Interferon Regulatory Factor 9 in Cerebral Ischemic Stroke
A Critical Role for Interferon Regulatory Factor 9 in Cerebral Ischemic Stroke
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干扰素调节因子 9 在脑缺血性中风中的关键作用
DOI：
10.1523/jneurosci.1545-14.2014
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发表时间：
2014-09-03
影响因子：
5.3
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Chen, Hou-Zao;Guo, Sen;Li, Hongliang
过去开发有效中风治疗方法的努力失败至少部分是因为这些治疗方法经常干扰基本的生理功能，即使它们针对病理生理事件，如炎症、兴奋性毒性和氧化应激。因此，直接靶向内源性神经保护或破坏性元素有望成为治疗这种破坏性疾病的潜在新方法。干扰素调节因子9 （IRF9）是一种调节先天免疫反应的转录因子，与神经病理学有关。本研究提供了IRF9直接介导雄性小鼠神经元死亡的新证据。在缺血/再灌注（I/R）的反应中，IRF9在神经元中积累。IRF9缺乏显著减轻脑卒中后神经元死亡和神经功能缺损，而神经元特异性的IRF9过表达使神经元对死亡敏感。组蛋白去乙酰化酶Sirt1在体内和体外都被确定为IRF9的一个新的负转录靶点。IRF9抑制Sirt1去乙酰化酶活性，最终导致p53介导的细胞死亡信号的乙酰化和激活。重要的是，Sirt1的遗传和药理学操作都有效地抵消了IRF9对卒中预后的病理生理影响。这些发现表明，在急性I/R应激下，IRF9不是激活延迟的先天免疫反应，而是通过下调Sirt1去乙酰化酶直接激活神经元死亡信号通路。
The failure of past efforts to develop effective stroke treatments is at least partially because these treatments often interfered with essential physiological functions, even though they are targeted toward pathophysiological events, such as inflammation, excitotoxicity, and oxidative stress. Thus, the direct targeting of endogenous neuroprotective or destructive elements holds promise as a potential new approach to treating this devastating condition. Interferon regulatory factor 9 (IRF9), a transcription factor that regulates innate immune responses, has been implicated in neurological pathology. Here, we provide new evidence that IRF9 directly mediates neuronal death in male mice. In response to ischemia/reperfusion (I/R), IRF9 accumulated in neurons. IRF9 deficiency markedly mitigated both poststroke neuronal death and neurological deficits, whereas the neuron-specific overexpression of IRF9 sensitized neurons to death. The histone deacetylase Sirt1 was identified as a novel negative transcriptional target of IRF9 both in vivo and in vitro. IRF9 inhibits Sirt1 deacetylase activity, culminating in the acetylation and activation of p53-mediated cell death signaling. Importantly, both the genetic and pharmacological manipulation of Sirt1 effectively counteracted the pathophysiological effects of IRF9 on stroke outcome. These findings indicate that, rather than activating a delayed innate immune response, IRF9 directly activates neuronal death signaling pathways through the downregulation of Sirt1 deacetylase in response to acute I/R stress.