AUTHOR=Jiang Rui , Huang Yuanyuan , Ye Rongcai , Zhang Yujian , Dong Meng , Zhang Hanlin , Cheng Ziyu , Zhang Zhi , Zhang Jiaqi , Zhang Qiaoli , Sun Gang , Jin Wanzhu 

TITLE=Brown adipocyte exosome - derived C22:6 inhibits the IL-1β signaling pathway to alleviate rheumatoid arthritis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1543288

DOI=10.3389/fimmu.2025.1543288

ISSN=1664-3224

ABSTRACT=IntroductionRheumatoid arthritis (RA) is an autoimmune disorder characterized by significant disability and teratogenic effects, for which there are few effective curative therapies. Exosomes derived from mesenchymal stem cells (MSCs) exhibit anti-inflammatory and tissue regenerative properties. This study aimed to investigate the therapeutic potential of exosomes derived from human classical interscapular brown adipocytes (hcBAC-exos) in alleviating symptoms of RA in a mouse model.MethodsWe established a mouse model of collagen-induced arthritis (CIA) to evaluate the efficacy of hcBAC-exos. Specifically, we assessed the degree of RA remission by applying vitamin E emulsion, as well as a mixture of vitamin E emulsion and hcBAC-exos, to the foot paws of CIA mice. Additionally, the effects of hcBAC-exos on pro-inflammatory cytokines in macrophages (RAW264.7 cells) were investigated at the cellular level. The active components of hcBAC-exos were analyzed via lipidomics, and the mechanism of their ability to inhibit inflammation was explored.ResultsAdministration of hcBAC-exos significantly reduced the expression of pro-inflammatory cytokines in macrophages. In the CIA mouse model, transdermal application of hcBAC-exos led to notable decreases in ankle swelling and the serum levels of IL-1β and TNFα (P < 0.5). Mechanistically, lipidomic analysis showed that Docosahexaenoic acid (C22:6) is highly enriched in hcBAC-exos. Furthermore, we found that C22:6 specifically inhibits IL-1β expression by binding to the amino acids Y183, S210, E265, S182, and R223 of TLR4, mutating these amino acids results in the loss of C22:6 binding activity to TLR4.DiscussionOur findings suggest that the hcBAC-exos-C22:6-TLR4-IL-1β signaling pathway plays a crucial role in the context of RA, indicating the potential clinical applications of hcBAC-exos in the treatment of inflammatory conditions such as rheumatoid arthritis.