Endometrial regenerative cell exosome-derived Sirtuin 6 alleviates ulcerative colitis by remodeling macrophage polarization

Abstract

Macrophage dysregulation is a feature of ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD). Exosomes generated from endometrial regenerative cells (ERCs) (ERC-Exos) may influence the immunological dysfunction associated with IBD. In immunological diseases, Sirtuin 6 (SIRT6) reduces NF-κB signalling due to its protective benefits. Building on these findings, this study investigates the function and mechanism of SIRT6 derived from ERC-Exos in mediating the relief of UC. Lentiviral transduction was used to achieve SIRT6-specific knockdown ERC-Exos (SIRT6-KD-ERC-Exos). Dextran sulphate sodium (DSS)-induced ulcerative colitis in mice was categorized into untreated (PBS control), ERC-Exo-treated, and SIRT6-KD-ERC-Exo-treated groups. Compared with the untreated group, ERC-Exo treatment significantly alleviated UC-caused weight loss, bloody stools, shortening of colon length, and pathological damage. Additionally, serum cytokine levels of IL-10 and TGF-β were increased, while IL-6 and TNF-α levels were decreased. Both in the spleen and the mesenteric lymph nodes, we discovered that ERC-Exos increased M2 macrophage polarisation and decreased M1 polarisation. However, when SIRT6 was knocked down in ERC-Exos, the protective effects were compromised. Additionally, SIRT6 in ERC-Exos reduced the number of M1-polarized macrophages by blocking the NF-κB signalling pathway. This research identifies exosomal SIRT6 derived from ERCs as a potent target for modulating macrophage polarization, underscoring a promising acellular therapeutic approach for inflammatory bowel disease.