Glycoprotein A33 deficiency: a new model of impaired intestinal epithelial barrier function and inflammatory disease
Publication Year 2015-08-01,Volume 8,Issue #8,Page 805-15
Journal Title
Dis Model Mech
Publication Type
Journal Article
The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food-hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33-/- mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33-/- mice exhibit impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33-/- mice also exhibit rapid onset and reduced resolution of DSS-induced colitis and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33-/- mice treated with AOM alone show no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33-/- mice display hypersensitivity to food allergens, a common co-morbidity in human patients with IBD. We propose that Gpa33-/- mice provide a valuable model to study the mechanisms linking intestinal permeability and multiple inflammatory pathologies. Moreover, this model could facilitate pre-clinical studies aimed at identifying drugs that restore barrier function.
WEHI Research Division(s)
Inflammation; Structural Biology; Development And Cancer
PubMed ID
NHMRC Grants
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Creation Date: 2015-06-15 09:53:31
Last Modified: 2015-08-13 03:12:37
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