Selective deletion of MyD88 signaling in α-SMA positive cells ameliorates experimental intestinal fibrosis via post-transcriptional regulation

Shuai Zhao, Dina Dejanovic, Peng Yao, Shardul Bhilocha, Tammy Sadler, Anja Schirbel, Gail West, Genevieve Doyon, Rocio Lopez, Ren Mao, Satya Kurada, Sara El Ouali, Guntram Grassl, Paul L. Fox, Michael Cruise, Daniel L. Worthley, Carol de la Motte, Claudio Fiocchi, Florian Rieder

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible α-SMA promoter Cre mice crossed with floxed MyD88 mice were subjected to chronic dextran sodium sulfate colitis. MyD88 was deleted prior to or after induction of colitis. Human intestinal myofibroblasts (HIMF) were exposed to various bacterial components and assessed for fibronectin (FN) and collagen I (Col1) production. RNA sequencing was performed. Post-transcriptional regulation was assessed by polysome profiling assay. Selective deletion of MyD88 in α-SMA-positive cells prior to, but not after induction of, experimental colitis decreased the degree of intestinal fibrosis. HIMF selectively responded to flagellin with enhanced FN or Col1 protein production in a MyD88-dependent manner. RNA sequencing suggested minimal transcriptional changes induced by flagellin in HIMF. Polysome profiling revealed higher proportions of FN and Col1 mRNA in the actively translated fractions of flagellin exposed HIMF, which was mediated by eIF2 alpha and 4EBP1. In conclusion, selectivity of flagellin-induced ECM secretion in HIMF is post-transcriptionally regulated. The results may represent a novel and targetable link between the gut microbiota and intestinal fibrogenesis.

Original languageEnglish
Pages (from-to)665-678
Number of pages14
JournalMucosal Immunology
Volume13
Issue number4
DOIs
Publication statusPublished or Issued - 1 Jul 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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