Nuclear localization of platelet activating factor receptor accounts for microglial phagocytosis in ischemic stroke.

Ischemic stroke (IS) is a leading cause of global morbidity and mortality. A critical strategy for improving the prognosis of IS involves mitigating neuronal loss to enhance neuroplasticity, with microglia playing a vital role in neuronal survival. The platelet activating factor receptor (PTAFR) participates in the pathological processes underlying IS; however, little is known about its mechanism in pathological stress. In this study, we investigated the potential role of PTAFR in regulating the microglia/macrophage phagocytosis of neurons, aiming to identify new therapeutic strategies for IS. The mRNA and protein expression levels of PTAFR were upregulated, peaking on day 5 post-ischemic stroke and gradually returning to baseline levels thereafter. PTAFR was found to mediate interactions between the microglia/macrophage and neurons in IS. Notably, the inhibition of phagocytosis of stressed-but-viable neurons following IS depends on the nuclear localization of PTAFR. Mechanistically, nuclear PTAFR recruited the transcription factor Specificity Protein 1 (SP1) to initiate the transcription of milk fat globule EGF factor 8 (MFGE8). In comparison to the membrane-impermeable antagonist Ginkgolide B, the membrane-permeable PTAFR antagonist Apafant significantly enhances neurological recovery in IS model mice. This effect is achieved by inhibiting PTAFR nuclear translocation, which reduces microglia/macrophage phagocytosis of stressed-but-viable neurons. Our findings provide insight into the mechanism of nuclear PTAFR-mediated microglia/macrophage phagocytosis and have significant implications for the selection of PTAFR antagonists in the treatment of ischemic stroke, particularly those targeting nuclear receptors.