Treg and intestinal myofibroblasts-derived Amphiregulin induced by TGF-β mediates intestinal fibrosis in Crohn's disease.

BACKGROUND

Intestinal fibrosis is a serious complication of Crohn's disease (CD), often resulting from chronic inflammation. However, the precise mechanisms through which inflammation induces intestinal fibrosis remain inadequately elucidated.

METHODS

A comprehensive single-cell atlas of full-thickness CD, provided by Dr. Florian Rieder, was subjected to reanalysis. Our study used a DSS-induced chronic colitis model in both wild-type (WT) and Areg mice. Additionally, a CD45RB CD4 T cell adoptive transfer model involving WT and Areg Treg cells (Tregs) was used. The expressions of AREG in CD with or without intestinal fibrosis, Tregs and human intestinal myofibroblasts (MFs) were determined. The effect of AREG on proliferation/migration/activation in human intestinal MFs was determined.

RESULTS

Several types of cells were differentially expressed between stricture and non-stricture CD. Among T cells, Tregs accounted for a larger proportion and were significantly increased in stenotic tissues of stricture CD. Although DSS-induced colitis was more severe in Areg mice, which developed less severe intestinal fibrosis compared with WT mice. The transfer of Areg Tregs resulted in less severe fibrosis in Rag mice than WT Tregs. Moreover, TGF-β stimulated AREG expression in Tregs and human intestinal MFs via activation of Smad3.

CONCLUSION

These findings demonstrated that AREG derived from Tregs and human intestinal MFs, induced by TGF-β, amplifies intestinal fibrotic reactions in experimental colitis as well as in human CD patients. Thus, the TGF-β-Smad3-AREG pathway could be a potential therapeutic target for treating fibrosis in CD.