CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.
CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.
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CircHivep2通过红藻氨酸诱导癫痫发作的小鼠中的miR-181a-5p/SOCS2信号传导促进小胶质细胞激活和炎症
DOI：
10.1111/jcmm.15894
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发表时间：
2020-11
影响因子：
5.3
通讯作者：
Jiahang S
中科院分区：
文献类型：
--
作者：
Xiaoying G;Guo M;Jie L;Yanmei Z;Ying C;Shengjie S;Haiyan G;Feixiang S;Sihua Q;Jiahang S
癫痫是一种以反复发作为特征的慢性脑部疾病。Circular RNA（circRNA）是一个新的内源性非编码RNA家族，已被提出用于调节基因表达。然而，缺乏关于circRNA在癫痫中作用的数据。在这项研究中，通过微阵列分析来评估circRNA谱。与对照组相比，红藻氨酸（KA）诱导癫痫发作的小鼠海马中共有627个circRNA上调，而892个下调。在KA诱导的癫痫发作小鼠的海马组织和KA处理后的BV-2小胶质细胞中，circHivep 2的表达显著下调。生物信息学分析预测，circHivep 2与miR-181 a-5 p相互作用以调节SOCS 2表达，这使用双荧光素酶报告基因测定进行了验证。此外，circHivep 2的过表达在体外显著抑制KA诱导的小胶质细胞活化和炎症因子的表达，这被miR-181 a-5 p阻断，而circHivep 2敲低在KA处理后进一步诱导小胶质细胞活化和BV-2小胶质细胞中促炎蛋白的释放。与对照外泌体相比，来自脂肪源性干细胞（ADSC）的circHivep 2+外泌体的应用对患有KA诱导的癫痫的小鼠的行为癫痫发作评分产生了显著的有益作用。circHivep 2+外泌体还在体内抑制小胶质细胞活化、炎症因子表达和miR-181 a-5 p/SOCS 2轴。我们的研究结果表明，circHivep 2通过干扰miR-181 a-5 p促进SOCS 2表达来调节癫痫进展中的小胶质细胞活化，这表明circHivep 2可以作为预防癫痫发展的治疗工具。
Epilepsy is a chronic brain disease characterized by recurrent seizures. Circular RNA (circRNA) is a novel family of endogenous non‐coding RNAs that have been proposed to regulate gene expression. However, there is a lack of data on the role of circRNA in epilepsy. In this study, the circRNA profiles were evaluated by microarray analysis. In total, 627 circRNAs were up‐regulated, whereas 892 were down‐regulated in the hippocampus in mice with kainic acid (KA)‐induced epileptic seizures compared with control. The expression of circHivep2 was significantly down‐regulated in hippocampus tissues of mice with KA‐induced epileptic seizures and BV‐2 microglia cells upon KA treatment. Bioinformatics analysis predicted that circHivep2 interacts with miR‐181a‐5p to regulate SOCS2 expression, which was validated using a dual‐luciferase reporter assay. Moreover, overexpression of circHivep2 significantly inhibited KA‐induced microglial activation and the expression of inflammatory factors in vitro, which was blocked by miR‐181a‐5p, whereas circHivep2 knockdown further induced microglia cell activation and the release of pro‐inflammatory proteins in BV‐2 microglia cells after KA treatment. The application of circHivep2+ exosomes derived from adipose‐derived stem cells (ADSCs) exerted significant beneficial effects on the behavioural seizure scores of mice with KA‐induced epilepsy compared to control exosomes. The circHivep2+ exosomes also inhibited microglial activation, the expression of inflammatory factors, and the miR‐181a‐5p/SOCS2 axis in vivo. Our results suggest that circHivep2 regulates microglia activation in the progression of epilepsy by interfering with miR‐181a‐5p to promote SOCS2 expression, indicating that circHivep2 may serve as a therapeutic tool to prevent the development of epilepsy.
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