Exogenous TSG-6 treatment alleviates DSS-induced colitis in mice by modulating Pou2f3 and promoting tuft cells differentiation.

BACKGROUND

Whereas intestinal epithelial barrier dysfunction is implicated in inflammatory bowel disease (IBD), the underlying mechanisms remain elusive. Tumor necrosis factor α stimulated gene 6 (TSG-6) is a secretory protein with anti-inflammatory properties. Our previous research demonstrated TSG-6 can relieve intestinal inflammation and mucosal damage. However, the underlying mechanism and targets remain unclear. This research sought to explore how TSG-6 regulates the intestinal epithelial barrier and its mechanistic role in experimental colitis.

METHODS

IBD mouse model was generated using dextran sodium sulfate (DSS), with or without intraperitoneal injection of TSG-6(100 µg/kg or 200 µg/kg). The effects of TSG-6 on colonic inflammation and intestinal barrier function were investigated. Label-free quantitative proteomic analysis was performed on intestinal samples to explore the mechanism and therapeutic target of TSG-6. Molecular interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence colocalization.

RESULTS

TSG-6 treatment significantly attenuated DSS-induced colitis symptoms and inflammatory cell infiltration. Microarray analysis revealed that TSG-6 decreased pro-inflammatory cytokine levels in colon tissue. TSG-6 restored the intestinal epithelial barrier through the promotion of intestinal epithelial cells (IECs) proliferation and mitigation of tight junctions (TJs) damage. Mechanistically, TSG-6 promoted tuft cells differentiation and increased interleukin-25 (IL-25) levels by directly binding to Pou class 2 homeobox 3(Pou2f3) and up-regulating its expression in the gut.

CONCLUSIONS

This study demonstrated TSG-6 as a positive regulator of tuft cells differentiation by interacting with Pou2f3, and the effectiveness of exogenous TSG-6 treatment on maintaining intestinal barrier integrity showed a promising potential for its clinical application.