Macrophages (Mφs) play a crucial role in the pathological progression of osteoarthritis (OA) by regulating inflammation and tissue repair. Decreasing pro-inflammatory M1-Mφs and increasing anti-inflammatory M2-Mφs can alleviate OA-related inflammation and promote cartilage repair. Apoptosis is a natural process associated with tissue repair. A large number of apoptotic bodies (ABs), a type of extracellular vesicle, are produced during apoptosis, and this is associated with a reduction in inflammation. However, the functions of apoptotic bodies remain largely unknown. In this study, we investigated the role of M2-Mφs-derived apoptotic bodies (M2-ABs) in regulating the M1/M2 balance of macrophages in a mouse model of OA. Our data show that M2-ABs can be targeted for uptake by M1-Mφs, and this reprograms M1-to-M2 phenotypes within 24 h. The M2-ABs significantly ameliorated the severity of OA, alleviated the M1-mediated pro-inflammatory environment, and inhibited chondrocyte apoptosis in mice. RNA-seq revealed that M2-ABs were enriched with miR-21–5p, a microRNA that is negatively correlated with articular cartilage degeneration. Inhibiting the function of miR-21–5p in M1-Mφs significantly reduced M2-ABs-guided M1-to-M2 reprogramming following in vitro cell transfection. Together, these results suggest that M2-derived apoptotic bodies can prevent articular cartilage damage and improve gait abnormalities in OA mice by reversing the inflammatory response caused by M1 macrophages. The mechanism underlying these findings may be related to miR-21-5p-regulated inhibition of inflammatory factors. The application of M2-ABs may represent a novel cell therapy, and could provide a valuable strategy for the treatment of OA and/or chronic inflammation.

巨噬细胞（Mφs）通过调节炎症和组织修复在骨关节炎（OA）的病理进展中发挥着至关重要的作用。减少促炎性M1-Mφs和增加抗炎性M2-Mφs可以减轻OA相关炎症并促进软骨修复。细胞凋亡是与组织修复相关的自然过程。细胞凋亡过程中会产生大量凋亡小体（AB），一种细胞外囊泡，这与炎症的减少有关。然而，凋亡小体的功能仍然很大程度上未知。在本研究中，我们研究了 M2-Mφs 衍生的凋亡小体 (M2-AB) 在 OA 小鼠模型中调节巨噬细胞 M1/M2 平衡的作用。我们的数据表明，M2-AB 可以被 M1-Mφ 靶向摄取，这会在 24 小时内将 M1 重新编程为 M2 表型。M2-AB 显着改善了 OA 的严重程度，减轻了 M1 介导的促炎环境，并抑制了小鼠的软骨细胞凋亡。RNA-seq 显示 M2-AB 富含 miR-21-5p，这是一种与关节软骨退变呈负相关的 microRNA。抑制 M1-Mφs 中 miR-21–5p 的功能可显着减少 M2-ABs 引导的 M1-to-M2 重编程体外细胞转染。总之，这些结果表明，M2 衍生的凋亡小体可以通过逆转 M1 巨噬细胞引起的炎症反应来预防 OA 小鼠的关节软骨损伤并改善步态异常。这些发现的机制可能与 miR-21-5p 调节的炎症因子抑制有关。M2-AB 的应用可能代表一种新型细胞疗法，并可为治疗 OA 和/或慢性炎症提供有价值的策略。