Zhang Mengyu, Wan Lei, Zhang Xiaojun, Wang Siyu, Li Feng, Yan Dawei
Anhui University of Traditional Chinese Medicine First Clinical Medical College, Hefei, Anhui, China.
First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, Anhui, China.
Front Immunol. 2025 Jul 17;16:1627389. doi: 10.3389/fimmu.2025.1627389. eCollection 2025.
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by persistent inflammation of the joint's synovial membrane. This inflammation leads to the degradation of joint cartilage and bone, resulting in joint dysfunction and deformity. Early symptoms of RA are often subtle, complicating timely diagnosis. Identifying potential markers for RA is therefore critical. PURPOSE AND STUDY DESIGN: This study aimed to explore the role of circular RNA CBLB (circ-CBLB) in RA by examining its influence on the Toll-like receptor 3/TNF receptor-associated factor 3 (TLR3/TRAF3) signaling axis and its effects on macrophage polarization through exosomes. RESULTS: We found that exosomes may contribute to macrophage polarization, as shown through exosome uptake assays and flow cytometry. Clinical data reveal low expression levels of circ-CBLB in rheumatoid arthritis patients, correlating negatively with immunoinflammatory indices. Overexpression of circ-CBLB was found to inhibit M1 macrophage polarization. Further, binding between circ-CBLB and TLR3 was confirmed using RNA Immunoprecipitation, RNA pulldown, Western blot analysis, immunofluorescence, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques. Inhibiting circ-CBLB or TLR3 demonstrated that the effects on macrophage polarization could be counteracted by introducing inhibitors or inducers for M2 macrophage polarization, underscoring the significant role of exosomal circ-CBLB in RA. CONCLUSION: Exosomal circ-CBLB plays a crucial role in inhibiting the TLR3/TRAF3 signaling pathway, thereby reducing M1 macrophage polarization in RA patients. These findings enhance our understanding of pathophysiology of RA and offer novel insights and methods for its diagnosis and treatment.
背景:类风湿性关节炎(RA)是一种慢性自身免疫性疾病,其特征是关节滑膜持续炎症。这种炎症会导致关节软骨和骨骼退化,从而导致关节功能障碍和畸形。RA的早期症状往往很轻微,这使得及时诊断变得复杂。因此,识别RA的潜在标志物至关重要。 目的和研究设计:本研究旨在通过研究环状RNA CBLB(circ-CBLB)对Toll样受体3/肿瘤坏死因子受体相关因子3(TLR3/TRAF3)信号轴的影响及其通过外泌体对巨噬细胞极化的作用,探讨circ-CBLB在RA中的作用。 结果:通过外泌体摄取试验和流式细胞术表明,我们发现外泌体可能有助于巨噬细胞极化。临床数据显示,类风湿性关节炎患者中circ-CBLB表达水平较低,与免疫炎症指标呈负相关。发现circ-CBLB的过表达可抑制M1巨噬细胞极化。此外,使用RNA免疫沉淀、RNA下拉、蛋白质免疫印迹分析、免疫荧光和定量逆转录聚合酶链反应(qRT-PCR)技术证实了circ-CBLB与TLR3之间的结合。抑制circ-CBLB或TLR3表明,通过引入M2巨噬细胞极化的抑制剂或诱导剂,可以抵消对巨噬细胞极化的影响,这突出了外泌体circ-CBLB在RA中的重要作用。 结论:外泌体circ-CBLB在抑制TLR3/TRAF3信号通路中起关键作用,从而减少RA患者的M1巨噬细胞极化。这些发现加深了我们对RA病理生理学的理解,并为其诊断和治疗提供了新的见解和方法。
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