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^RASF) 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^RASF) 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^RASF, EVs^RASF without CCR5 (EVs^RASF-CCR5), or EVs^M which encapsulated the CCR5 antagonist Maraviroc. The results demonstrated that EVs^RASF-CCR5 reversed the catabolic effect of EVs^RASF on hRA-CHs. EVs^RASF 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^RASF-CCR5 and EVs^M treatment mitigated these effects, suggesting a detrimental role of CCR5 in EVs^RASF-mediated RA pathogenesis. These findings highlight the critical role of CCR5 in mediating the pro-inflammatory and destructive effects of EVs^RASF 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^RASF 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.