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Original article
IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo
  1. Kristina Scheibe1,
  2. Ingo Backert1,
  3. Stefan Wirtz1,
  4. Axel Hueber2,
  5. Georg Schett2,
  6. Michael Vieth3,
  7. Hans Christian Probst4,
  8. Tobias Bopp4,
  9. Markus F Neurath1,
  10. Clemens Neufert1
  1. 1First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany
  2. 2Third Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany
  3. 3Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
  4. 4Institute for Immunology, University Medical Center Mainz, Mainz, Germany
  1. Correspondence to Dr Clemens Neufert, First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander Universitätsklinikum Erlangen-Nürnberg, Ulmenweg 18, Erlangen D-91054, Germany; clemens.neufert{at}


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.


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