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

Scheibe K, Backert I, Wirtz S, Hueber A, Schett G, Vieth M, Probst HC, Bopp T, Neurath M, Neufert C (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Gut BMJ Publishing Group

Publisher: BMJ Publishing Group

DOI: 10.1136/gutjnl-2015-310374

Abstract

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.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.Expression of IL-36? and IL-36? was significantly elevated in active human IBD and experimental colitis. While IL-36? was predominantly detected in nuclei of the intestinal epithelium, IL-36? 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.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.

Authors with CRIS profile

Kristina Koop Interdisziplinäres Zentrum für Klinische Forschung IZKF-Förderlinien Ingo Backert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Axel Hueber Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Clemens Neufert Medizinische Fakultät

How to cite

APA:

Scheibe, K., Backert, I., Wirtz, S., Hueber, A., Schett, G., Vieth, M.,... Neufert, C. (2016). IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo. Gut. https://doi.org/10.1136/gutjnl-2015-310374

MLA:

Scheibe, Kristina, et al. "IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo." Gut (2016).

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