中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (8): 1769-1775.doi: 10.4103/1673-5374.332154

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

microRNA-455-5p减轻脑缺血再灌注后的神经炎症

  

  • 出版日期:2022-08-15 发布日期:2022-01-22
  • 基金资助:
    国家自然科学基金项目（82071283，81671130）；上海交通大学医学工程交叉研究基金项目（YG2017MS83）；上海市科委医学指导科技支撑项目（19411968400）

microRNA-455-5p alleviates neuroinflammation in cerebral ischemia/reperfusion injury

Jian-Song Zhang1, 2, #, Pin-Pin Hou1, #, Shuai Shao2, #, Anatol Manaenko3, Zhi-Peng Xiao2, Yan Chen4, Bing Zhao2, Feng Jia2, Xiao-Hua Zhang2, Qi-Yong Mei5, *, Qin Hu1, 2, *   

  1. 1Central Laboratory, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 4Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 5Department of Neurosurgery, Changzheng Hospital, the Second Military Medical University, Shanghai, China
  • Online:2022-08-15 Published:2022-01-22
  • Contact: Qi-Yong Mei, MD, PhD, meiqiyong@smmu.edu.cn; Qin Hu, MD, PhD, huqinle20010709@126.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82071283 (to QH) and 81671130 (to QH); Medical Engineering Cross Research Foundation of Shanghai Jiao Tong University of China, No. YG2017MS83 (to QH); and from Shanghai Municipal Science and Technology Commission Medical Guidance Science and Technology Support Project of China, No. 19411968400 (to QYM).

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摘要：

神经炎症是导致脑缺血再灌注后脑损伤发展的主要病理生理因素之一。miR-455-5p在缺血性卒中后下调，因而被认为是缺血后神经元损伤的潜在生物标志物和治疗靶点。然而，尚未评估miR-455-5p的具体作用和机制。实验以缺血后神经元以大脑中动脉闭塞1h并再灌注建立脑缺血再灌注模型，并与损伤前2h或损伤后1和1h脑室注射miR-455-5p类似物Agomir-455-5p、抑制剂antagomir-455-5p或其阴性对照。结果显示，脑缺血再灌注可降低小鼠脑组织和外周血中miR-455-5p的表达。agomir-455-5p预处理可增加大脑中miR-455-5p的水平，减少脑梗死体积，并改善神经功能。进一步以原代培养的小胶质细胞暴露于氧糖剥夺环境3h，再复氧21h在体外模拟脑缺血再灌注探索及作用机制，发现microRNA-455-5p的有益作用至少部分是在mRNA和蛋白水平方面可降低C-C趋化因子受体5的表达，抑制小胶质细胞的活化，减少炎症因子肿瘤坏死因素α和白细胞介素1β的产生而实现的。实验结果提示miR-455-5p是一种治疗脑缺血/再灌注损伤的潜在生物标志物和治疗靶点，且其可通过抑制C-C 趋化因子受体 5表达，减少神经炎症反应，从而减轻脑脑缺血再灌注诱导的损伤。

https://orcid.org/0000-0002-2270-8822 (Qin Hu)

关键词: 神经炎症, microRNA-455-5p, agomiR-455-5p, C-C趋化因子受体5, 脑缺血再灌注损伤, 缺血性脑卒中, 小胶质细胞, 血脑屏障, 生物标志物, 预处理

Abstract: Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion. Downregulation of microRNA (miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia. However, the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated. In this study, mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion. Agomir-455-5p, antagomir-455-5p, and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion (MCAO). The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood. Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue, reduced the cerebral infarct volume, and improved neurological function. Furthermore, primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion. miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels, inhibited microglia activation, and reduced the production of the inflammatory factors tumor necrosis factor-α and interleukin-1β. These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response.

Key words: agomiR-455-5p, biomarker, blood-brain barrier, C-C chemokine receptor type 5, ischemia/reperfusion injury, ischemic stroke, microglia, microRNA-455-5p, neuroinflammation, pretreatment