IFITM1 promotes microglial polarization and NLRP3 inflammasome activation in ischemic stroke through up-regulating c-FOS.

Microglial polarization and the NLRP3 inflammasome play critical roles in the pathology of ischemic stroke (IS). Regulation of microglial polarization towards M2 type has become a potential therapy approach for M2 type has become a potential therapy approach for treating IS. The current study demonstrated IFITM1 was markedly upregulated in microglia in the Distal middle cerebral artery (dMCAO) model. This research sought to assess the protective potential of IFITM1 knockdown in IS and to study its downstream regulatory mechanisms. The dMCAO mice model and oxygen-glucose deprivation/reoxygenation (OGD/R) BV2 cell model were constructed to imitate IS injury. The GSE148350 dataset was utilized to screen for differentially expressed genes in IS. Immunofluorescence, western blotting, and ELISA were utilized to evaluated activation level of NLRP3 inflammasome. RT-qPCR was applied to evaluated gene expression associated with the M1/M2 phenotypes and glycolysis of microglia. After treatment with dMCAO and OGD/R, IFITM1 expression was significantly upregulated. Knockdown of IFITM1 significantly inhibited M1 markers and promoted M2 markers of microglia. Additionally, knockdown of IFITM1 obviously inhibited the activation of the NLRP3 inflammasome and glycolysis. The expression of c-FOS was markedly raised following OGD/R, but was obviously inhibited by knockdown of IFITM1. Rescue experiments showed that knockdown of IFITM1 inhibited the NLRP3 inflammasome activation and M1 polarization of microglia by suppressing c-FOS expression. Knockdown of IFITM1 alleviated brain infarction, brain edema, and neurological damage in dMCAO mice. These results suggest that the absence of IFITM1 alleviates brain injury induced by dMCAO, inhibiting NLRP3 inflammasome activation and glycolysis of microglia through suppressing c-FOS expression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-025-00832-5.