Research Progress on Efferocytosis Dysfunction in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic disease characterized by chronic synovial inflammation, immune dysregulation, and progressive joint destruction. Macrophages serve as the core immune effector cells within the RA synovium, and their functional abnormalities are pivotal in sustaining inflammation and tissue damage. Efferocytosis refers to the highly efficient, immunosuppressive clearance of apoptotic cells by macrophages, forming the foundation for tissue homeostasis and the resolution of inflammation. However, the RA synovium exhibits a pronounced defect in efferocytosis, resulting in delayed clearance of apoptotic cells—particularly neutrophils—thereby precipitating secondary necrosis, the release of damage-associated molecular patterns (DAMPs), exposure of self-antigens, and chronic inflammation, ultimately establishing a vicious cycle. Preclinical studies targeting this mechanism have demonstrated that either activating TAM receptors or pro-resolving lipid mediators to enhance efferocytic signaling, or blocking its inhibitory pathways, can significantly attenuate inflammation and protect joints. Consequently, a deep analysis of the efferocytosis regulatory network and the development of “pro-resolving” rather than merely “anti-inflammatory” therapeutic strategies offer new prospects for the precision treatment of RA.

类风湿关节炎（Rheumatoid arthritis, RA）是一类以慢性滑膜炎症、免疫失调及进行性关节破坏为特征的全身性疾病。巨噬细胞是RA滑膜内的核心免疫效应细胞，其功能异常在维持炎症与组织损伤过程中发挥关键作用。胞葬作用（efferocytosis）指巨噬细胞对凋亡细胞进行的高效、免疫抑制性清除，是组织稳态维持与炎症消退的基础。然而，RA滑膜存在显著的胞葬作用缺陷，导致凋亡细胞（尤其是中性粒细胞）的清除延迟，进而引发继发性坏死、损伤相关分子模式（damage-associated molecular patterns, DAMPs）释放、自身抗原暴露及慢性炎症，最终形成恶性循环。针对该机制的临床前研究表明，激活TAM受体或促消退脂质介质以增强胞葬信号通路，或阻断其抑制通路，均可显著减轻炎症并保护关节。因此，深入解析胞葬作用调控网络，并开发“促消退”而非单纯“抗炎”的治疗策略，为RA的精准治疗带来了新的前景。