title: IRF4 is a novel mediator for neuronal survival in ischaemic stroke.
abstract: Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4-SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4-SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors: S
authors: S
authors: Guo
authors: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Z-Z
authors: ZZ
authors: Li
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors: D-S
authors: DS
authors: Jiang
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors: Y Y
authors: YY
authors: Lu
authors: College of Life Sciences, Wuhan University, Wuhan, China.
authors: Y
authors: Y
authors: Liu
authors: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: L
authors: L
authors: Gao
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors: S-M
authors: SM
authors: Zhang
authors: 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, China.
authors: H
authors: H
authors: Lei
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors: L-H
authors: LH
authors: Zhu
authors: College of Life Sciences, Wuhan University, Wuhan, China.
authors: X-D
authors: XD
authors: Zhang
authors: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: D-P
authors: DP
authors: Liu
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors: H
authors: H
authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D020521:Stroke / Q000235:genetics* / Q000473:pathology; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4