Suppressing nuclear translocation of microglial PKM2 confers neuroprotection via downregulation of neuroinflammation after mouse cerebral ischemia–reperfusion injury

[Display omitted] •PKM2 expression was increased in the microglia after cerebral ischemia–reperfusion (I/R) injury.•Microglial polarization-mediated pro-inflammatory effect was mediated by PKM2 after I/R.•PKM2-dependent Histone H3/Hif-1α modifications contributed the expression of CCL2 and induced up-regulation of microglial polarization.•Inhibiting nuclear translocation of microglial PKM2 reduced ischemia-induced pro-inflammation and promoted neuronal survival. Pyruvate kinase M2 (PKM2) is a key metabolic enzyme. Yet, its role in cerebral ischemia injury remains unclear. In this study we demonstrated that PKM2 expression was increased in the microglia after mouse cerebral ischemia–reperfusion (I/R) injury. We found that microglial polarization-mediated pro-inflammatory effect was mediated by PKM2 after cerebral I/R. Mechanistically, our results revealed that nuclear PKM2 mediated ischemia-induced microglial polarization through association with acetyl-H3K9. Hif-1α mediated the effect of nuclear PKM2/histone H3 on microglial polarization. PKM2-dependent Histone H3/Hif-1α modifications contributed the expression of CCL2 and induced up-regulation of microglial polarization in peri-infarct, resulting in neuroinflammation. Inhibiting nuclear translocation of microglial PKM2 reduced ischemia-induced pro-inflammation and promoted neuronal survival. Together, this study identifies nucleus PKM2 as a crucial mediator for regulating ischemia-induced neuroinflammation, suggesting PKM2 as a potential therapeutic target in ischemic stroke.