Microglial PRMT2IP alleviates ischemia-induced brain injury.

Microglia serve as the principal instigators of neuroinflammatory cascades following ischemic stroke. We here demonstrated that PRMT2IP (previously named as 1700017B05Rik in mice and C15orf39 in humans) is essential for modulating microglial activation and functional responses in ischemic stroke. Mendelian randomization (MR) analysis demonstrated a causal relationship between downregulation of human PRMT2IP expression and an elevated risk of ischemic stroke. Mouse PRMT2IP expression was downregulated in ischemic microglia. Critically, PRMT2IP overexpression provided a protective role in reducing cerebral ischemia injury, while PRMT2IP knockout showed significantly worsened outcomes. Mechanistically, PRMT2IP interacts with PRMT2 and inhibits the activation of the NF-κB signaling pathway by PRMT2-IκBα signaling axis, ultimately reducing the expression of inflammatory factors IL-6 and TNFα. In conclusion, our results suggest that microglial PRMT2IP, as a key negative regulator of microglial inflammatory response, alleviates ischemia-induced brain injury. Thus, up-regulation of PRMT2IP expression may provide a therapeutic strategy to attenuate deleterious neuroinflammation post-stroke.