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.
Original language | English (US) |
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Pages (from-to) | 89-102 |
Number of pages | 14 |
Journal | Gastroenterology |
Volume | 164 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2023 |
Keywords
- Effector CD4T Cells
- Inflammatory Bowel Diseases
- Intestinal Inflammation
- Intestinal Myofibroblasts
ASJC Scopus subject areas
- Hepatology
- Gastroenterology