CircRNA_09505 aggravates inflammation and joint damage in collagen-induced arthritis mice via miR-6089/AKT1/NF-κB axis.
CircRNA_09505 aggravates inflammation and joint damage in collagen-induced arthritis mice via miR-6089/AKT1/NF-κB axis.
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CircRNA_09505 通过 miR-6089/AKT1/NF-kappa B 轴加重胶原诱导的关节炎小鼠的炎症和关节损伤
DOI：
10.1038/s41419-020-03038-z
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发表时间：
2020-10-07
影响因子：
9
通讯作者：
Xu D
中科院分区：
文献类型：
--
作者：
Yang J;Cheng M;Gu B;Wang J;Yan S;Xu D
类风湿性关节炎（RA）的发病机制涉及大量的环状RNA（circular RNA，circRNA），但其在免疫和炎症调节中的功能和潜在的分子机制尚不清楚。本研究探讨了circRNA_09505在RA中的作用及其机制。采用实时荧光定量PCR和荧光原位杂交（FISH）技术检测巨噬细胞中circRNA_09505的定量表达和定位。通过使用巨噬细胞模型和胶原诱导的关节炎（CIA）小鼠在体外和体内研究了circRNA_09505对炎症的改变作用。使用荧光素酶报告基因测定和RNA结合蛋白免疫沉淀（RIP）来确认通过生物信息学分析预测的circRNA_09505/miR-6089 ceRNA网络。与对照相比，circRNA_09505在来自RA患者的外周血单个核细胞（PBMC）中的表达上调。当circRNA_09505在巨噬细胞中上调时，增殖和细胞周期显著促进，而circRNA_09505的敲低抑制巨噬细胞增殖和细胞周期进展。此外，circRNA_09505还可以作为巨噬细胞中miR-6089的miRNA海绵，通过ceRNA机制促进TNF-α、IL-6和IL-12的产生。此外，AKT 1是miR-6089的直接靶点。CircRNA_09505可通过IκBα/NF-κB信号通路作为miR-6089海绵促进巨噬细胞中AKT 1的表达。最有趣的是，敲低circRNA_09505显著减轻CIA小鼠体内的关节炎和炎症。这些数据支持以下假设：在CIA小鼠中，circRNA_09505可以作为miR-6089海绵发挥作用，并通过miR-6089/AKT 1/NF-κB轴调节炎症。
A number of circular RNAs (circRNAs) have been implicated in rheumatoid arthritis (RA) pathogenesis; however, little is known about their function and hidden molecular mechanism in immune and inflammation regulation. We investigated the role and the underlying mechanism of circRNA_09505 in RA in this study. Real-time PCR and fluorescence in situ hybridization (FISH) are adopted to estimate the quantitative expression and localization of circRNA_09505 in macrophages. The altering effect of circRNA_09505 on inflammation is investigated in vitro and in vivo by use of macrophage cell models and collagen-induced arthritis (CIA) mice. Luciferase reporter assay and RNA-binding protein immunoprecipitation (RIP) are used to confirm the circRNA_09505/miR-6089 ceRNA network predicted by bioinformatics analysis. Compared with controls, the expression of circRNA_09505 is upregulated in peripheral blood mononuclear cells (PBMCs) from patients with RA. The proliferation and cell cycle are significantly promoted when circRNA_09505 is upregulated in macrophages, whereas knockdown of circRNA_09505 inhibits macrophage proliferation and cell- cycle progression. Besides, circRNA_09505 can act as a miRNA sponge for miR-6089 in macrophages, and promote the production of TNF-α, IL-6, and IL-12 through ceRNA mechanism. Moreover, AKT1 is a direct target of miR-6089. CircRNA_09505 can promote AKT1 expression by acting as a miR-6089 sponge via IκBα/NF-κB signaling pathway in macrophages. Most interestingly, knockdown of circRNA_09505 significantly alleviates arthritis and inflammation in vivo in CIA mice. These data support the hypothesis that circRNA_09505 can function as a miR-6089 sponge and regulate inflammation via miR-6089/AKT1/NF-κB axis in CIA mice.