Regulation of Microglial Activation by Wnt/β-Catenin Signaling After Global Cerebral Ischemia in Mice

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(GFP/+) 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/beta-catenin signaling after cerebral ischemia. Downregulation of Wnt/beta-catenin signaling using Wnt antagonist XAV939 during 20 min ischemia promoted microglial de-ramification and proliferation. In contrast, enhancing Wnt/beta-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/beta-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.