IL-33-Stimulated Macrophage Exosomes Ameliorate TNBS-Induced Colitis by Upregulating Wnt/β-catenin Signaling

Inflammatory bowel disease (IBD) is a debilitating condition with increasing global prevalence, significantly elevating the risk of colorectal cancer. Current immunosuppressive therapies often fall short, achieving mucosal healing in only a limited number of patients. M2-polarized macrophages are recognized for their critical role in mucosal repair and maintaining intestinal microenvironment homeostasis. Leveraging these reparative properties, particularly through secreted factors like exosomes, represents a promising strategy to address the unmet need for effective therapies that promote epithelial barrier function and healing in IBD.

Researchers investigated the therapeutic potential of macrophage-derived exosomes in a murine model of IBD. Colitis was induced in mice via intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Following induction, mice were treated with exosomes isolated from either IL-33-treated macrophages (IL-33-Exos) or untreated macrophages (PBS-Exos). The study assessed the amelioration of inflammatory intestinal mucosal injury and improvement in intestinal barrier dysfunction as primary endpoints. Mechanistic investigations focused on intestinal epithelial cell damage and the activation of specific signaling pathways using techniques like western blot and immunohistochemistry.

Treatment with IL-33-Exos markedly ameliorated inflammatory intestinal mucosal injury in the TNBS-induced colitis model. The exosomes also significantly improved intestinal barrier dysfunction, a critical aspect of IBD pathology. Furthermore, IL-33-Exos were found to mitigate intestinal epithelial cell damage, thereby preserving intestinal mucosal integrity. This protective effect was observed across various histological assessments. Mechanistic studies revealed that the beneficial effects of IL-33-Exos were strongly implicated in the upregulation of Wnt/β-catenin signaling within intestinal epithelial cells. This pathway is crucial for cell proliferation, differentiation, and tissue repair. The findings suggest a direct role for IL-33-Exos in promoting epithelial repair processes.

IL-33-Exos significantly improved intestinal barrier dysfunction and mitigated epithelial cell damage, preserving mucosal integrity in TNBS-induced colitis.