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

Xiaojing Zhao, Wenjing Yang, Tianming Yu, Yu Yu, Xiufang Cui, Zheng Zhou, Hui Yang, Yanbo Yu, Anthony J. Bilotta, Suxia Yao, Jimin Xu, Jia Zhou, Gregory S. Yochum, Walter A. Koltun, Austin Portolese, Defu Zeng, Jingwu Xie, Iryna V. Pinchuk, Hongjie Zhang, Yingzi Cong

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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 languageEnglish (US)
Pages (from-to)89-102
Number of pages14
Issue number1
StatePublished - Jan 2023

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology


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