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Gut 62:1714-1723 doi:10.1136/gutjnl-2011-301785
  • Experimental colitis
  • Original article

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

Open Access
  1. Bernhard Ryffel1,13
  1. 1CNRS and University, UMR7355, Molecular Immunology, Orleans, France and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, RSA
  2. 2The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia
  3. 3CNRS, IPBS, Toulouse, France
  4. 4Toulouse University, UPS, F-31077 Toulouse, France
  5. 5Department of Autoimmunity, Transplantation and Inflammation, Novartis Institute for Biomedical Research, Basel, Switzerland
  6. 6Institut Pasteur de Lille, Lille, France
  7. 7University Lille Nord de France, Lille, France
  8. 8CNRS, UMR 8204, Lille, France
  9. 9Inserm, U1019, Lille, France
  10. 10Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland
  11. 11School of Medicine, Trinity College, Dublin, Ireland
  12. 12Inserm U954, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
  13. 13Artimmune SAS, Orléans, France
  1. Correspondence to Dr Bernhard Ryffel, UMR 6218, CNRS, Orléans University, F-45071 Orléans, France; bryffel{at}cnrs-orleans.fr
  • Received 14 September 2012
  • Accepted 8 October 2012
  • Published Online First 21 November 2012

Abstract

Objective Inflammatory bowel diseases (IBD) have been intrinsically linked to a deregulated cytokine network, but novel therapeutic principles are urgently needed. Here we identify the interleukin (IL)-33 and its receptor ST2 as key negative regulators of wound healing and permeability in the colon of mice.

Design Expression of IL-33 and ST2 was determined by qRT-PCR, ELISA, immunohistochemistry and western-blot analysis. Wild-type and St2−/− mice were used in wound healing experiments and in two experimental models of IBD triggered by 2,4,6-trinitrobenzene sulphonic acid or dextran sodium sulphate (DSS). Neutralisation of ST2 was performed by using a specific blocking antibody.

Results Nuclear localisation and enhanced expression of IL-33 in myofibroblasts and enterocytes was linked to disease involvement independently of inflammation, while the expression of ST2 was primarily restricted to the colonic epithelia. In two experimental models of IBD, genetic ablation of ST2 significantly improved signs of colitis, while a sustained epithelial expression of the cyto-protective factor connexin-43 was observed in DSS-treated St2-deficient mice. Unexpectedly, absence of ST2 in non-hematopoietic cells was sufficient to protect against colitis. Consistently, specific inhibition of endogenous ST2-mediated signalling by treatment with neutralising antibody improved DSS-induced colitis. In addition, IL-33 treatment impaired epithelial barrier permeability in vitro and in vivo, whereas absence of ST2 enhanced wound healing response upon acute mechanical injury in the colon.

Conclusions Our study unveiled a novel non-hematopoietic function of IL-33 in epithelial barrier function and wound healing. Therefore, blocking the IL-33/ST2 axis may represent an efficient therapy in IBD.

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