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. 2017 May;66(5):823-838.
doi: 10.1136/gutjnl-2015-310374. Epub 2016 Jan 18.

IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo

Kristina Scheibe  1 , Ingo Backert  1 , Stefan Wirtz  1 , Axel Hueber  2 , Georg Schett  2 , Michael Vieth  3 , Hans Christian Probst  4 , Tobias Bopp  4 , Markus F Neurath  1 , Clemens Neufert  1
Affiliations

IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo

Kristina Scheibe et al. Gut. 2017 May.

Abstract

Objective: Interleukin (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.

Design: We 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.

Results: Expression 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.

Conclusions: IL-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.

Keywords: INFLAMMATORY BOWEL DISEASE; INTERLEUKINS; MUCOSAL INJURY.

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