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

作者：Kristina Scheibe, Ingo Backert, Stefan J. Wirtz, Axel J. Hueber, Georg Andreas Schett, Michael W. Vieth, Hans Christian Probst, Tobias Bopp, Markus Friedrich Neurath, Clemens Neufert · 发表于：Gut · 年份：2016 · DOI：10.1136/gutjnl-2015-310374 · 被引用次数：202 · 研究领域：Psoriasis: Treatment and Pathogenesis、Dermatology and Skin Diseases、Cytokine Signaling Pathways and Interactions

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 accelera...