Xia Qian, Mao Meng, Zhan Gaofeng, Luo Zhenzhao, Zhao Yin, Li Xing
Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China.
iScience. 2023 May 25;26(6):106953. doi: 10.1016/j.isci.2023.106953. eCollection 2023 Jun 16.
Recent evidences have implicated that SENP3 is a deSUMOylase which possesses neuronal damage effects in cerebral ischemia. However, its role in microglia remains poorly understood. Here, we found that SENP3 was upregulated in the peri-infarct areas of mice following ischemic stroke. Furthermore, knockdown of SENP3 significantly inhibits the expression of proinflammatory cytokines and chemokines in microglial cells. Mechanistically, SENP3 can bind and then mediated the deSUMOylation of c-Jun, which activated its transcriptional activity, ultimately followed by the activation of MAPK/AP-1 signaling pathway. In addition, microglia-specific SENP3 knockdown alleviated ischemia-induced neuronal damage, and markedly diminished infract volume, ameliorated sensorimotor and cognitive function in animals subjected to ischemic stroke. These results indicated SENP3 functions as a novel regulator of microglia-induced neuroinflammation by activating the MAPK/AP-1 signaling pathway via mediating the deSUMOylation of c-Jun. Interventions of SENP3 expression or its interaction with c-Jun would be a new and promising therapeutic strategy for ischemic stroke.
近期证据表明,SENP3是一种去SUMO化酶,在脑缺血中具有神经损伤作用。然而,其在小胶质细胞中的作用仍知之甚少。在此,我们发现SENP3在缺血性脑卒中后小鼠的梗死周边区域上调。此外,敲低SENP3可显著抑制小胶质细胞中促炎细胞因子和趋化因子的表达。机制上,SENP3可结合并介导c-Jun的去SUMO化,激活其转录活性,最终激活MAPK/AP-1信号通路。此外,小胶质细胞特异性敲低SENP3可减轻缺血诱导的神经损伤,并显著减小梗死体积,改善缺血性脑卒中动物的感觉运动和认知功能。这些结果表明,SENP3通过介导c-Jun的去SUMO化激活MAPK/AP-1信号通路,作为小胶质细胞诱导的神经炎症的新型调节因子发挥作用。干预SENP3的表达或其与c-Jun的相互作用将是缺血性脑卒中一种新的、有前景的治疗策略。