Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation

Scheibe K, Kersten C, Schmied A, Vieth M, Primbs T, Carlé BE, Knieling F, Claussen J, Klimowicz AC, Zheng J, Baum P, Meyer S, Schürmann S, Friedrich O, Waldner M, Rath T, Wirtz S, Kollias G, Ekici AB, Atreya R, Raymond EL, Mbow ML, Neurath M, Neufert C (2018)

Publication Type: Journal article

Publication year: 2018

Journal

DOI: 10.1053/j.gastro.2018.11.029

Abstract

BACKGROUND & AIMS: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) frequently resulting in functional damage, bowel obstruction, and surgery. Interleukin 36 (IL36) is a group of cytokines in the IL1 family with inflammatory effects. We studied expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in development of intestinal fibrosis in human tissues and mice. METHODS: We obtained intestinal tissues from 92 patients with Crohn´s disease (CD), 48 patients with ulcerative colitis (UC), and 26 patients without inflammatory bowel diseases (controls). Tissues were analyzed by histology to detect fibrosis and immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R and we studied intestinal tissues from Il1rl2-/- mice; colitis and fibrosis was induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2-/- to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied. RESULTS: Mucosal and submucosal tissues from patients with CD or UC had higher levels of collagens including type VI collagen compared to tissues from controls. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed alpha smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2-/- mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis following administration of DSS or TNBS, but bone marrow cells from Il1rl2-/- mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation. CONCLUSION: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD, compared with controls. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.

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Involved external institutions

LMU Klinikum Germany (DE) Boehringer Ingelheim Pharma GmbH & Co. KG Germany (DE) Klinikum Bayreuth Germany (DE) Biomedical Sciences Research Center "Alexander Fleming" Greece (GR)

How to cite

APA:

Scheibe, K., Kersten, C., Schmied, A., Vieth, M., Primbs, T., Carlé, B.-E.,... Neufert, C. (2018). Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation. Gastroenterology. https://doi.org/10.1053/j.gastro.2018.11.029

MLA:

Scheibe, Kristina, et al. "Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation." Gastroenterology (2018).

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