Zhu Yuanyuan, Tong Juan, Jiang Jianzhong, Shi Keyun, Xie Jing, Zhu Yan, Li Yuefeng, Xu Yuhao
Department of Geriatrics, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214221, Jiangsu, China.
Department of Neuroimaging Laboratory, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
Metab Brain Dis. 2025 Mar 13;40(3):147. doi: 10.1007/s11011-025-01572-3.
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.
慢性脑灌注不足诱导的白质损伤（WMI）是血管性认知障碍的一个重要原因。新出现的证据表明，miR-218可能参与了WMI的发病机制。然而，对于miR-218与慢性灌注不足诱导的WMI之间的关系仍了解不足。我们的研究在临床、动物和细胞水平上研究了miR-218与慢性灌注不足诱导的WMI之间的关系。我们发现，临床WMI患者血清miR-218表达升高，对WMI具有一定的诊断效能，且与WMI程度、认知评分及血清炎症因子相关。此外，我们构建了双侧颈动脉狭窄（BCAS）小鼠模型以模拟慢性灌注不足诱导的WMI，并检测到BCAS小鼠白质中miR-218表达增加。向BCAS小鼠白质注射Lv-sh-miR-218后，观察到认知障碍和WMI均有改善。此外，Lv-sh-miR-218还减少了小胶质细胞的M1极化和白质内的神经炎症。随后，我们通过生物信息学分析和荧光素酶报告基因测定证实SOCS3是miR-218的特异性靶标。向BCAS小鼠白质注射LV-SOCS3也导致认知障碍和WMI得到改善，同时小胶质细胞的M1极化和神经炎症减少。此外，在原代培养的小胶质细胞中，我们证明慢性缺氧后，miR-218通过SOCS3/STAT3途径调节炎症因子。总之，我们目前的结果表明，miR-218水平升高与慢性灌注不足诱导的WMI之间存在密切关联，下调miR-218表达可通过上调SOCS3改善神经炎症，从而改善WMI和认知障碍。
