title: A critical role for interferon regulatory factor 9 in cerebral ischemic stroke.
abstract: 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.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Zuo-Zhi
authors.initials: ZZ
authors.lastname: Li
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xiang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Virology, Department of Immunology and Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China, and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China, liudp@pumc.edu.cn lihl@whu.edu.cn.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China, liudp@pumc.edu.cn lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000378:metabolism; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D056564:Sirtuin 1; D016159:Tumor Suppressor Protein p53; C470545:Sirt1 protein, mouse; C494228:Isgf3g protein, mouse
keywords: IRF9; Sirt1; neuroapoptosis; p53; stroke