Suppression of miR-218 promotes SOCS3 expression to alleviate cognitive impairment and white matter injury after chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion-induced white matter injury (WMI) is a significant cause of vascular cognitive impairment. Emerging evidence suggests that miR-218 may be involved in the pathogenesis of WMI. However, understanding of the relationship between miR-218 and chronic hypoperfusion-induced WMI remains insufficient. Our study investigated the relationship between miR-218 and chronic hypoperfusion-induced WMI at clinical, animal, and cellular levels. We found that serum miR-218 expression was elevated in clinical WMI patients, had a certain diagnostic efficacy for WMI, and was correlated with the degree of WMI, cognitive scores, and serum inflammatory factors. In addition, we constructed a mouse model with bilateral carotid artery stenosis (BCAS) to simulate chronic hypoperfusion-induced WMI and detected an increase in miR-218 expression in the white matter of BCAS mice. Following administration of Lv-sh-miR-218 to the white matter of BCAS mice, improvements were observed in both cognitive impairment and WMI. Furthermore, Lv-sh-miR-218 also reduced M1 polarization of microglia and neuroinflammation within the white matter. Subsequently, we confirmed that SOCS3 is the specific target of miR-218 through bioinformatics analysis and luciferase reporter gene assays. Injection of LV-SOCS3 into the white matter also led to improvements in cognitive impairment and WMI in BCAS mice, along with reduced M1 polarization of microglia and neuroinflammation. Moreover, in primary cultured microglia cells, we demonstrated that after chronic hypoxia, miR-218 regulates inflammatory factors through the SOCS3/STAT3 pathway. In summary, our current results indicate a strong correlation between elevated miR-218 levels and chronic hypoperfusion-induced WMI, and downregulation of miR-218 expression can improve neuroinflammation by upregulating SOCS3, thereby ameliorating WMI and cognitive impairment.