Elucidating the molecular mechanisms of CCR5-containing extracellular vesicles in vitro and in a rat model of experimental Rheumatoid arthritis.

Extracellular vesicles from Rheumatoid arthritis (RA) derived synovial fibroblasts (EVs) have been implicated in the pathogenesis of RA, acting as mediators of cell-to-cell communication. This study aimed to elucidate the role of the chemokine receptor CCR5 and EVs positive for CCR5 (EVs) in RA, focusing on their impact on cartilage destruction and bone erosion in a rat model of Adjuvant-induced arthritis (AIA). In vivo experiments were conducted using AIA rats, treated with either EVs, EVs without CCR5 (EVs), or EVs which encapsulated the CCR5 antagonist Maraviroc. The results demonstrated that EVs reversed the catabolic effect of EVs on hRA-CHs. EVs accelerated cartilage destruction and bone erosion in the AIA rats, as evidenced by increased arthritis scores, joint damage, and NF-κB activation. In contrast, EVs and EVs treatment mitigated these effects, suggesting a detrimental role of CCR5 in EVs-mediated RA pathogenesis. These findings highlight the critical role of CCR5 in mediating the pro-inflammatory and destructive effects of EVs in RA, suggesting that targeting CCR5 may represent a novel therapeutic strategy for RA management. In conclusion, this study provides valuable insights into one of the molecular mechanisms underlying RA pathogenesis, emphasizing the importance of EVs and CCR5 in mediating synovial inflammation and joint destruction. The results underscore the potential of CCR5 as a therapeutic target, opening avenues for the development of targeted interventions in RA treatment with synovial fibroblast derived EVs serving as a convenient, stabilizing vehicle for delivering Maraviroc into the RA affected joint tissues.