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

Sedhom, Mamdouh A. K., Pichery, Melanie, Murdoch, Jenna R., Foligne, Benoit, Ortega, Nathalie, Normand, Sylvain, Mertz, Kirsten, Sanmugalingam, Devika, Brault, Lea, Grandjean, Teddy, Lefrancais, Emma, Fallon, Padraic G., Quesniaux, Valerie, Peyrin-Biroulet, Laurent, Cathomas, Gieri, Junt, Tobias, Chamaillard, Mathias, Girard, Jean-Philippe and Ryffel, Bernhard (2013) Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut, 62 12: 1714-1723. doi:10.1136/gutjnl-2011-301785


Author Sedhom, Mamdouh A. K.
Pichery, Melanie
Murdoch, Jenna R.
Foligne, Benoit
Ortega, Nathalie
Normand, Sylvain
Mertz, Kirsten
Sanmugalingam, Devika
Brault, Lea
Grandjean, Teddy
Lefrancais, Emma
Fallon, Padraic G.
Quesniaux, Valerie
Peyrin-Biroulet, Laurent
Cathomas, Gieri
Junt, Tobias
Chamaillard, Mathias
Girard, Jean-Philippe
Ryffel, Bernhard
Title Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice
Journal name Gut   Check publisher's open access policy
ISSN 0017-5749
1468-3288
Publication date 2013-12-01
Year available 2012
Sub-type Article (original research)
DOI 10.1136/gutjnl-2011-301785
Open Access Status DOI
Volume 62
Issue 12
Start page 1714
End page 1723
Total pages 10
Place of publication London, United Kingdom
Publisher BMJ
Collection year 2014
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
 
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