CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures

Gao Xiaoying; Mian Guo; Liu Jie; Zhu Yanmei; Cui Ying; Shu Shengjie; Gou Haiyan; Sun Feixiang; Qi Sihua; Sun Jiahang

doi:10.1111/jcmm.15894

CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures

J Cell Mol Med. 2020 Nov;24(22):12980-12993. doi: 10.1111/jcmm.15894. Epub 2020 Oct 1.

Authors

Gao Xiaoying¹, Mian Guo², Liu Jie², Zhu Yanmei³, Cui Ying⁴, Shu Shengjie⁵, Gou Haiyan³, Sun Feixiang², Qi Sihua¹, Sun Jiahang²

Affiliations

¹ Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
² Department of Neurosurgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
³ Department of Radiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
⁴ Department of Neurology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
⁵ Department of Imageology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.

Abstract

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.

Keywords: circular RNAs; epilepsy; inflammatory response; miR-181a-5p; microglia activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism
Animals
Biotinylation
Cell Line
DNA-Binding Proteins / genetics*
Epilepsy / metabolism
Exosomes / metabolism
Gene Expression Profiling
Gene Expression Regulation
Hippocampus / metabolism
In Situ Hybridization, Fluorescence
Inflammation / drug therapy*
Kainic Acid
Male
Mice
Mice, Inbred C57BL
MicroRNAs / metabolism*
Microglia / drug effects*
Oligonucleotide Array Sequence Analysis
RNA, Circular / genetics*
RNA, Long Noncoding / genetics
Seizures / chemically induced
Seizures / metabolism*
Signal Transduction
Suppressor of Cytokine Signaling Proteins / metabolism*

Substances

DNA-Binding Proteins
Hivep2 protein, mouse
MicroRNAs
RNA, Circular
RNA, Long Noncoding
Socs2 protein, mouse
Suppressor of Cytokine Signaling Proteins
mirn181 microRNA, mouse
Kainic Acid