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Role of m6A modification and novel circ_0066715/ miR-486-5p/ ETS1 axis in rheumatoid arthritis macrophage
Lei Wan1,2, Jian Liu1,2, Chuanbing Huang1
1The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230038, China.
Abstract:
Rheumatoid arthritis (RA) is a systemic disease dominated by inflammatory synovitis. RA synovial macrophages tend undergo M1-type macrophage polarization. Then, polarized M1-type macrophages secrete abundant pro-inflammatory cytokines, causing joint and cartilage destruction. N6-methyladenosine (m6A) methylation modification, circular RNA (circRNA), microRNA (miRNA), messenger RNA (mRNA), etc. are involved in the inflammatory response of RA. We found that there is an imbalance of inflammatory polarization in RA, which is manifested by a sharp increase in inflammatory markers and a high inflammatory response. Here, we show that RA was closely associated with low expression of circ_0066715. The overexpression of circ_0066715 significantly increased the ETS1 levels in RA-FLS cells, decreased cytokine secretion by M1-type macrophages, elevated M2-type cytokines, and inhibited FLS proliferation. Interestingly, the overexpression of miR-486-5p significantly suppressed the attenuation of the cell function and the effect on M1 macrophage polarization caused by circ_0066715 positive expression. WTAP may be involved in the methylation process of ETS1 in RA. ETS1 m6A methylation levels were altered upon WTAP intervention. The overexpression or interference of circ_0066715 decreased or increased WTAP expression. Our findings provide a novel circRNA/miRNA/mRNA regulatory axis and m6A regulatory mechanism involved in the process of RA macrophage polarization, thereby providing a powerful diagnostic and therapeutic strategy for RA treatment.
Insights
Low circ_0066715 expression is linked to rheumatoid arthritis (RA) macrophage polarization. Restoring circ_0066715 may offer a new therapeutic strategy for RA by regulating inflammatory responses.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammatory synovitis.
- RA involves M1-type macrophage polarization, leading to pro-inflammatory cytokine release and joint destruction.
- N6-methyladenosine (m6A) methylation, circRNAs, miRNAs, and mRNAs play roles in RA's inflammatory response.
Purpose of the Study:
- To investigate the role of circ_0066715 in RA macrophage polarization.
- To elucidate the regulatory axis involving circ_0066715, miR-486-5p, and ETS1 in RA.
- To explore the involvement of WTAP-mediated m6A methylation in RA pathogenesis.
Main Methods:
- Analysis of circ_0066715 expression in RA.
- Overexpression studies of circ_0066715 and miR-486-5p in RA-FLS cells.
- Assessment of cytokine secretion, FLS proliferation, and macrophage polarization.
- Investigation of WTAP's role in ETS1 m6A methylation.
Main Results:
- RA is associated with decreased circ_0066715 expression.
- Overexpression of circ_0066715 increased ETS1, reduced M1 macrophage polarization and cytokine secretion, and inhibited FLS proliferation.
- miR-486-5p overexpression counteracted the effects of circ_0066715.
- WTAP influenced ETS1 m6A methylation, and circ_0066715 affected WTAP expression.
Conclusions:
- A novel circRNA/miRNA/mRNA regulatory axis (circ_0066715/miR-486-5p/ETS1) and an m6A mechanism involving WTAP are implicated in RA macrophage polarization.
- These findings suggest circ_0066715 as a potential diagnostic marker and therapeutic target for RA.
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