title: IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo.
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-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.
  
  
  
  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.affiliation: First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Scheibe
authors.affiliation: First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Backert
authors.affiliation: First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Third Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hueber
authors.affiliation: Third Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.affiliation: Institute for Immunology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Probst
authors.affiliation: Institute for Immunology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nüernberg, Erlangen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Neufert
mesh_terms: D000818:Animals; D040502:Calgranulin B / Q000096:biosynthesis; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008024:Ligands; D000071068:Lipocalin-2 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014945:Wound Healing
chemical_list: D040502:Calgranulin B; D018925:Chemokines; D016207:Cytokines; D016264:Dextran Sulfate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007375:Interleukin-1; D015850:Interleukin-6; D008024:Ligands; D000071068:Lipocalin-2; D053594:Myeloid Differentiation Factor 88; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; C508586:IL36A protein, human; C508589:IL36G protein, human; C507780:Myd88 protein, mouse; C571244:interleukin-36 receptor, human; C569500:Il1rl2 protein, mouse
keywords: INFLAMMATORY BOWEL DISEASE; INTERLEUKINS; MUCOSAL INJURY