自身抗体（ACPAs）与类风湿性关节炎（RA）病情严重程度密切相关，但其诱导RA病情发展机制研究较少。关节滑膜及血管翳中大量浸润巨噬细胞是介导RA炎症及软骨损伤主要因素之一。申请者前期工作发现：RA患者关节液中巨噬细胞亚型比例严重失调，且伴有miR-let-7a表达降低；ACPAs抑制RA患者单个核细胞miR-let-7a表达，活化IRF5促进巨噬细胞向M1型转换。miR-let-7a通过影响IL-6、PAK、C/EBP-δ诱导巨噬细胞亚型转换。在此基础上，本项目验证miR-let-7a介导ACPAs活化巨噬细胞，探讨其作用靶点、干扰的信号传导途径，明确ACPAs活化巨噬细胞作用机制；利用miR-let-7a agomir验证miR-let-7a在小鼠关节炎病情发展中作用、探讨机制，为阐明ACPAs在RA病情发展中的作用奠定基础，也为临床寻找治疗RA的新靶点提供依据。

Anti-citrullinated protein antibodies (ACPAs) are highly specific for RA and a powerful tool for its diagnosis and predicting disease severity. ACPAs’ roles in RA pathogenesis is poorly understood. Macrophages are of central importance in RA due to their prominent numbers in the inflamed synovial membrane and at the cartilage-pannus junction. Our results demonstrated that macrophage subset disequilibrium occurred in RA patient synovial fluids, accompany with miR-let-7a low-expression. ACPAs suppress let-7a expression in monocytes from patients with rheumatoid arthritis, and activated IRF5, induced macrophages to polarize to M1 subtypes. IL-6, PAK and C/EBP-δ are a direct target gene for the miR-let-7a. On this basis, in this study, we investigate the target gene for the miR-let-7a and the transcript factor in ACPAs-induced macrophage, and demonstrate the role of miR-let-7a in the development of RA pathogenesis.

自身抗体（ACPAs）是类风湿性关节炎（RA）的辅助诊断指标之一，且与RA病情严重程度密切相关。为探讨ACPAs对RA病情影响的作用机制，本研究搜集临床样本，观察RA患者关节液巨噬细胞中miR-let7a表达、ACPAs诱导的巨噬细胞及ACPAs诱导的小鼠类风湿性关节炎模型HMGA2、PI3K、IRF5表达，探讨ACPAs对RA病情影响的作用机制。结果表明：与OA相比，RA患者关节液中miR-let7a表达降低，ACPAs(160 IU/mL)可抑制RA患者巨噬细胞miR-let7a表达，进一步研究发现：miR-let7a可通过直接作用于HMGA2，通过PI3K，抑制IRF5，影响ACPAs诱导的巨噬细胞活性。在ACPAs诱导的小鼠关节炎模型中，随病情发展，肿胀关节及脾脏中miR-let7a表达明显降低，而HMGA2、PI3K、IRF5表达升高。将miR-let7a模拟物注入RA小鼠体内，并未缓解RA鼠病情发展。本项目研究结果表明：RA患者体内巨噬细胞miR-let7a的表达降低，miR-let7a作用于HMGA2介导ACPAs诱导的巨噬细胞向M1型转化，且与小鼠关节炎模型的病情严重程度密切相关。