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IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo
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IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo
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IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo
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Journal Article
IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo
2017
Overview
ObjectiveInterleukin (IL)-36R signalling plays a proinflammatory role in different organs including the skin, but the expression of IL-36R ligands and their molecular function in intestinal inflammation are largely unknown.DesignWe studied the characteristics of IL-36R ligand expression in IBDs and experimental colitis. The functional role of IL-36R signalling in the intestine was addressed in experimental colitis and wound healing models in vivo by using mice with defective IL-36R signalling (IL-36R−/−) or Myd88, neutralising anti-IL-36R antibodies, recombinant IL-36R ligands and RNA-seq genome expression analysis.ResultsExpression of IL-36α and IL-36γ was significantly elevated in active human IBD and experimental colitis. While IL-36γ was predominantly detected in nuclei of the intestinal epithelium, IL-36α was mainly found in the cytoplasm of CD14+ inflammatory macrophages. Functional studies showed that defective IL-36R signalling causes high susceptibility to acute dextran sodium sulfate colitis and impairs wound healing. Mechanistically, IL-36R ligands released upon mucosal damage activated IL-36R+ colonic fibroblasts via Myd88 thereby inducing expression of chemokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6. Moreover, they induced proliferation of intestinal epithelial cells (IECs) and expression of the antimicrobial protein lipocalin 2. Finally, treatment of experimental intestinal wounds with IL-36R ligands significantly accelerated mucosal healing in vivo.ConclusionsIL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.
Publisher
BMJ Publishing Group LTD
Subject
/ Animals
/ Biopsy
/ Calgranulin B - biosynthesis
/ Colitis
/ Colitis - chemically induced
/ Colon
/ Dextran
/ Epithelial Cells - metabolism
/ Genomes
/ Granulocyte-macrophage colony-stimulating factor
/ Granulocyte-Macrophage Colony-Stimulating Factor - metabolism
/ Humans
/ Inflammatory Bowel Diseases - metabolism
/ Intestinal Mucosa - metabolism
/ Ligands
/ Mice
/ Mucosa
/ Myeloid Differentiation Factor 88 - genetics
/ Myeloid Differentiation Factor 88 - metabolism
/ Receptors, Interleukin - metabolism
/ Receptors, Interleukin-1 - genetics
/ Receptors, Interleukin-1 - metabolism
/ RNA
/ Rodents
/ Signal Transduction - genetics
/ Skin
/ Sodium
