Targeting microglial PPARα ameliorates the outcome of ischemic stroke by enhancing interaction with infiltrating peripheral monocytes/macrophages

作者：Tong Ren, Maoshu Zhu, Xilin Jiang, Lanxi Xu, Hao Jin, Yu Zhou, Yun Zhao, Rengong Zhuo, Wen‐Jun Li, Caixia Chen, Peng Lü, Xin Jin, Ying Li, Lichao Yang · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.115875 · 被引用次数：13 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Peroxisome Proliferator-Activated Receptors、Immune cells in cancer

The interaction between infiltrating immune cells and brain-resident cells is critical for inducing an inflammatory response to ischemic stroke. However, the direct effects of CD11b + CD45 int microglia in the brain on infiltrating CD11b + CD45 high Ly6G − monocytes/macrophages (Mos/MΦs) and the precise molecular mechanisms underlying these effects after acute ischemic stroke (AIS) remain unknown. Here, ischemia-induced microglial peroxisome proliferator-activated receptor-alpha (PPARα) downregulation was found to be critical for enhancing the inflammatory response and exacerbating ischemic brain injury by priming peripheral pro-inflammatory Mo/MΦ infiltration. The targeted microglial PPARα signal exerted neuroprotective effects on ischemic stroke by protecting blood-brain barrier (BBB) integrity and inhibiting the infiltration of innate immune cells. Furthermore, overexpression of microglia-specific PPARα exerted neuroprotective effects by enhancing the interleukin (IL)-4 signal-mediated crosstalk of microglia-MΦs. Therefore, our study reveals that ischemia-induced microglial PPARα deficiency expands the inflammatory response and exacerbates ischemic brain injury by enhancing the interaction with infiltrating peripheral Mos/MΦs and suggests that targeting microglial PPARα is a potential therapeutic strategy for improving acute cerebral ischemic injury.