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

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...

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Bibliographic Details
Published in:Mucosal immunology 2020-07, Vol.13 (4), p.665-678
Main Authors: Zhao, Shuai, Dejanovic, Dina, Yao, Peng, Bhilocha, Shardul, Sadler, Tammy, Schirbel, Anja, West, Gail, Doyon, Genevieve, Lopez, Rocio, Mao, Ren, Kurada, Satya, El Ouali, Sara, Grassl, Guntram, Fox, Paul L, Cruise, Michael, Worthley, Daniel L, de la Motte, Carol, Fiocchi, Claudio, Rieder, Florian
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Biomarkers
Cells, Cultured
Colitis
Collagen (type I)
Dextran
Disease Susceptibility
Extracellular Matrix
Fibroblasts - metabolism
Fibronectin
Fibrosis
Flagellin
Fluorescent Antibody Technique
Gene Expression Profiling
Gene Expression Regulation
Gene regulation
Humans
Immunohistochemistry
Inflammatory bowel disease
Inflammatory bowel diseases
Intestinal microflora
Intestinal Mucosa - immunology
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Intestine
Mesenchyme
Mice
Microbiota
MyD88 protein
Myeloid Differentiation Factor 88 - deficiency
Post-transcription
RNA Processing, Post-Transcriptional
Signal Transduction
Sodium sulfate
Stricture
Tamoxifen
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Summary: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.
ISSN:1933-0219
1935-3456
DOI:10.1038/s41385-020-0259-9