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

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^highLy6G^- 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.