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Abstract
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.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease with unclear pathogenesis[1]
Screening differentially expressed circular RNA (circRNA) in RA Differentially expressed circRNAs in peripheral blood mononuclear cells (PBMCs) from three patients and three controls were screened by RNA sequencing
There is sufficient evidence that a number of circRNAs are aberrantly expressed in RA, which may participate in RA pathogenesis[17,18]
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease with unclear pathogenesis[1]. Abnormal phenotype and function of those cells play crucial roles in regulating autoimmunity and inflammation. Both innate and Official journal of the Cell Death Differentiation Association. Yang et al Cell Death and Disease (2020)11:833 macrophages from inflamed tissue is a promising strategy for RA treatment. Mounting data have implicated that noncoding RNAs (ncRNAs) primarily including microRNA (miRNA), circular RNA (circRNA), and long ncRNA (lncRNA) play critical roles in mediating inflammation and immune regulation in autoimmune diseases[7,8,9]. Some ncRNAs encapsulated in extracellular vesicles can be found in peripheral circulation and confer modifying effects on joint lesions and tissue regeneration via cell-tocell communications in rheumatic diseases[10,11]. The precise mechanism for circRNA/miRNA ceRNA network in RA has not been fully understood
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