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