MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation

Jingshu Ni  ¹ , Xiaoyu Wang  ¹ , Shuangshuang Chen  ¹ , Huihui Liu  ² , Yun Wang  ¹ , Xingshun Xu  ³ , Jian Cheng  ³ , Jia Jia  ⁴ , Xuechu Zhen  ⁵

Affiliations

• ¹ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
• ² The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
• ³ Institute of Neuroscience, Soochow University, Suzhou, China; The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
• ⁴ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: jiajia@suda.edu.cn.
• ⁵ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China; College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China. Electronic address: zhenxuechu@suda.edu.cn.

Abstract

The present study was designed to reveal the potential role of let-7c-5p, a highly conserved miRNA in stroke. We found that the content of let-7c-5p was significantly decreased in the plasma of patients with ischemic stroke as well as in experimental animals. Moreover, we also observed a significant decrease of let-7c-5p in ipsilateral cortex and striatum in mice that were subjected to middle cerebral artery occlusion (MCAO) at 24h reperfusion. Overexpression of let-7c-5p via ICV injection decreased the infarction volume and attenuated the neurological deficits, and most interestingly, inhibited microglial activation. To further explore the mechanism, we checked let-7c-5p expression in BV2 cells and primary microglia in an OGD condition and in LPS-induced microglial activation. The results indicated that decreased let-7c-5p was evidenced in the activated microglia. Overexpression of let-7c-5p in BV2 cells remarkably inhibited the microglial activation. The inhibition of microglial activation by overexpression of let-7c-5p was also observed in mice with experimental stroke, which is in line with the decreased infarction volume and improved neurological deficits. We identified that let-7c-5p directly targeted to the 3′-untranslated region of the caspase 3 mRNA to reduce caspase 3 levels, which may underline the miRNA – modulated microglial activity. The present study revealed that suppression of microglia activation by let-7c-5p overexpression may be involved in the protection effects of ischemic damage. The mechanism may include the miRNA-mediated caspase 3 pathway.

Keywords: Ischemic stroke; Let-7c-5p; MicroRNA; Microglia.