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Neutralization of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice

Sedhom, Mamdouh A.K. and Pichery, Melanie and Murdoch, Jenna and Foligne, Benoit and Ortega, Nathalie and Normand, Sylvain and Mertz, Kirsten and Butler, Matt and Brault, Lea and Lefrancais, Emma and Fallon, Padraic G. and Quesniaux, Valerie and Cathomas, Gieri and Junt, Tobias and Chamaillard, Mathias and Girard, Jean-Philippe and Ryffel, Bernhard (2012) Neutralization of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut. ISSN 0017-5749

Abstract

Novel therapeutic principles are urgently needed for inflammatory bowel diseases (IBD), pathologies that have been linked to a deregulated inflammatory cytokine network. Here we identify the interleukin (IL)-1-like cytokine IL-33 and its receptor ST2 as key negative regulators of wound healing and epithelial permeability in the colon of mice. In IBD patients, nuclear expression of IL-33 was enhanced in endothelial cells, myofibroblasts and enterocytes, while the expression of ST2 was primarily restricted to the colonic epithelia. A similar expression pattern was observed in two experimental models of IBD in mice, where genetic or pharmacological ablation of ST2 significantly improved signs of colitis. Conversely, administration of recombinant IL-33 to mice exacerbated intestinal inflammation and permeability, while a sustained epithelial expression of the cyto-protective factor connexin-43 was observed in DSS-treated St2-deficient mice. Consistently, absence of ST2 enhanced wound healing response in a model of acute in vivo injury in the colon. This highlights a negative regulatory role of the IL-33/ST2 axis in self-renewal of the colonic epithelia. Therefore, neutralization of ST2 or IL-33 may represent a novel therapeutic strategy for IBD.

Item Type: Article
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Keywords: antibody-targeted therapy, cytokines, epithelial barrier, epithelial permeability, experimental colitis
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6186

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