Cheeloo College of Medicine, Jinan Central Hospital, Shandong University, Jinan, China.
FASEB J. 2021 Dec;35(12):e22014. doi: 10.1096/fj.202100993R.
Spinal cord injury (SCI) is a complex pathological change that includes primary SCI and gradually evolves into secondary SCI. Accumulating evidence demonstrates that circular RNAs (circRNAs) are involved in the pathology of a variety of neurological diseases and injuries. However, the characteristics and function of circRNAs in SCI have yet to be elucidated. Although previous research demonstrated that circPrkcsh induces astrocytes to produce inflammatory factors and chemokines, the precise function and mechanism of circPrkcsh in microglia after SCI remains unknown. In this study, we constructed a mouse model of SCI by applying a SCI impactor. Quantitative Real-time PCR and Fluorescence in situ hybridization analysis revealed that circPrkcsh was upregulated in the microglia of SCI mice when compared to sham-operated mice. Gain- or loss-of-function experiments and in vivo assays further indicated that circPrkcsh promotes microglia M1 polarization both in vivo and in vitro. Furthermore, bioinformatics analysis, dual-luciferase assays, and RNA immunoprecipitation assays, confirmed that circPrkcsh serves as a competing endogenous RNA (ceRNA) to promote the expression of MEKK1 mRNA by sponging miR-488. Double knockout rescue experiments further showed that circPrkcsh regulates the MEKK1/JNK/p38 MAPK pathway via miR-488. Our research provides a better understanding of the mechanism of circPrkcsh in SCI and demonstrates that the circPrkcsh/miR-488/Mekk1 axis is a promising regulatory method for the treatment of SCI.
脊髓损伤 (SCI) 是一种复杂的病理变化，包括原发性 SCI 和逐渐发展为继发性 SCI。越来越多的证据表明，环状 RNA（circRNAs）参与多种神经疾病和损伤的病理过程。然而，circRNAs 在 SCI 中的特征和功能尚未阐明。尽管先前的研究表明 circPrkcsh 诱导星形胶质细胞产生炎症因子和趋化因子，但 circPrkcsh 在 SCI 后小胶质细胞中的确切功能和机制仍不清楚。在这项研究中，我们通过应用 SCI 撞击器构建了 SCI 小鼠模型。定量实时 PCR 和荧光原位杂交分析显示，与假手术组相比，SCI 小鼠的小胶质细胞中 circPrkcsh 上调。增益或功能丧失实验以及体内实验进一步表明，circPrkcsh 促进体内和体外小胶质细胞 M1 极化。此外，生物信息学分析、双荧光素酶报告基因实验和 RNA 免疫沉淀实验证实，circPrkcsh 作为竞争性内源性 RNA（ceRNA）通过海绵吸附 miR-488 促进 MEKK1 mRNA 的表达。双敲除挽救实验进一步表明，circPrkcsh 通过 miR-488 调节 MEKK1/JNK/p38 MAPK 通路。我们的研究提供了对 circPrkcsh 在 SCI 中作用机制的更好理解，并表明 circPrkcsh/miR-488/Mekk1 轴是治疗 SCI 的有前途的调节方法。
