Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts

Abstract

Background & aims: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood.

Methods: In this study, T-cell transfer model with wild-type (WT) and Areg^-/- Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg^-/- mice were used. CD4⁺ T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis.

Results: Although Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred into Tcrβxδ^-/- mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg^-/- mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer of Areg^-/- Th17 cells induced less severe fibrosis in Tcrβxδ^-/- mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4⁺ T cells in fibrotic sites compared with nonfibrotic sites from patients with CD.

Conclusions: These findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD.

Keywords: Effector CD4(+)T Cells; Inflammatory Bowel Diseases; Intestinal Inflammation; Intestinal Myofibroblasts.