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Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice
- Source :
- Gut, Gut, BMJ Publishing Group, 2013, 62 (12), pp.1714-1723. ⟨10.1136/gutjnl-2011-301785⟩, Gut, 2013, 62 (12), pp.1714-1723. ⟨10.1136/gutjnl-2011-301785⟩
- Publication Year :
- 2013
- Publisher :
- HAL CCSD, 2013.
-
Abstract
- International audience; 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.
- Subjects :
- Male
Epithelial Barrier
[SDV]Life Sciences [q-bio]
Blotting, Western
Experimental Colitis
Inflammation
Enzyme-Linked Immunosorbent Assay
Real-Time Polymerase Chain Reaction
Permeability
03 medical and health sciences
Mice
0302 clinical medicine
Intestinal mucosa
In vivo
Blocking antibody
medicine
Animals
Humans
Colitis
Intestinal Mucosa
Antibody Targeted Therapy
030304 developmental biology
0303 health sciences
Wound Healing
business.industry
Interleukins
Gastroenterology
Interleukin
Receptors, Interleukin
medicine.disease
Interleukin-33
Interleukin-1 Receptor-Like 1 Protein
3. Good health
[SDV] Life Sciences [q-bio]
Interleukin 33
Mice, Inbred C57BL
Disease Models, Animal
030220 oncology & carcinogenesis
Immunology
Cytokines
Colitis, Ulcerative
medicine.symptom
Caco-2 Cells
Wound healing
business
Epithelial Permeability
Subjects
Details
- Language :
- English
- ISSN :
- 00175749 and 14683288
- Database :
- OpenAIRE
- Journal :
- Gut, Gut, BMJ Publishing Group, 2013, 62 (12), pp.1714-1723. ⟨10.1136/gutjnl-2011-301785⟩, Gut, 2013, 62 (12), pp.1714-1723. ⟨10.1136/gutjnl-2011-301785⟩
- Accession number :
- edsair.doi.dedup.....aa690605ba279161fa24c1615ba37131