Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, 730000, China.
Mol Neurobiol. 2024 Jan;61(1):308-325. doi: 10.1007/s12035-023-03557-8. Epub 2023 Aug 22.
Microglia are immunocompetent cells in the central nervous system. Following cerebral ischemia, microglia will be rapidly activated and undergo proliferation, morphological transformation, and changes in gene expression and function. At present, the regulatory mechanisms of microglial activation following ischemia remain largely unclear. In this study, we took advantage of CX3CR1 fluorescent mice and a global cerebral ischemia-reperfusion model to investigate the mechanisms of microglial activation following different degrees of global ischemia. Our results showed that the proliferation of microglia was gated by the degree of ischemia. Marked microglial de-ramification and proliferation were observed after 60 min of ischemia but not in transient ischemia (20 min). Immunohistology, qRT-PCR, and Western blotting analysis showed that microglial activation was accompanied with a reduction in Wnt/β-catenin signaling after cerebral ischemia. Downregulation of Wnt/β-catenin signaling using Wnt antagonist XAV939 during 20 min ischemia promoted microglial de-ramification and proliferation. In contrast, enhancing Wnt/β-catenin signaling using Wnt agonist LiCl during 60 min ischemia-reduced microglial de-ramification and proliferation. Importantly, we found that Wnt agonist inhibited inflammation in the ischemic brain and was conducive to animal behavioral recovery. Collectively, these data demonstrated that Wnt/β-catenin signaling played a key role in microglial activation following cerebral ischemia, and regulating microglial activation may be a potential therapeutic strategy for the treatment of ischemic stroke.
小胶质细胞是中枢神经系统中具有免疫功能的细胞。脑缺血后，小胶质细胞将被迅速激活，并经历增殖、形态转化以及基因表达和功能的变化。目前，缺血后小胶质细胞激活的调节机制在很大程度上仍不清楚。在这项研究中，我们利用 CX3CR1 荧光小鼠和全脑缺血再灌注模型，研究了不同程度全脑缺血后小胶质细胞激活的机制。我们的结果表明，小胶质细胞的增殖受到缺血程度的控制。在 60 分钟的缺血后观察到明显的小胶质细胞去分枝和增殖，但在短暂性缺血（20 分钟）中没有观察到。免疫组织化学、qRT-PCR 和 Western blot 分析表明，脑缺血后小胶质细胞激活伴随着 Wnt/β-catenin 信号的减少。在 20 分钟的缺血期间使用 Wnt 拮抗剂 XAV939 下调 Wnt/β-catenin 信号会促进小胶质细胞去分枝和增殖。相比之下，在 60 分钟的缺血期间使用 Wnt 激动剂 LiCl 增强 Wnt/β-catenin 信号会减少小胶质细胞去分枝和增殖。重要的是，我们发现 Wnt 激动剂抑制了缺血性大脑中的炎症，并有利于动物行为的恢复。总之，这些数据表明，Wnt/β-catenin 信号在脑缺血后小胶质细胞激活中起关键作用，调节小胶质细胞激活可能是治疗缺血性中风的一种潜在治疗策略。
