CYTIP promotes pro-inflammatory activation of microglia through interaction with LRRFIP2 following ischemic stroke.

Microglia-mediated neuroinflammation is a critical contributor to cerebral ischemia/reperfusion (I/R) injury. However, the functional heterogeneity of microglia presents significant challenges in defining therapeutic signatures. By integrating single-nucleus RNA sequencing (snRNA-seq) of a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model with bulk RNA sequencing of BV2 microglia subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), we identified Cytip as a highly upregulated core regulator within a transient "primed" microglial subpopulation upon I/R insult. Functional validation demonstrated that Cytip promotes a pro-inflammatory microglial phenotype and exacerbates oxidative stress, whereas its knockdown ameliorates these OGD/R-induced dysfunctions. Mechanistically, immunoprecipitation-mass spectrometry revealed that CYTIP directly interacts with LRRFIP2. Overexpression of LRRFIP2 counteracted CYTIP-mediated pathogenic effects, significantly suppressing microglial inflammation and IL-1β production. These findings suggest that CYTIP promotes microglial inflammatory responses via the NLRP3/LRRFIP2 axis, highlighting the CYTIP-LRRFIP2 interaction as a promising therapeutic target for post-stroke recovery.