Glycoprotein A33 deficiency: a new model of impaired intestinal epithelial barrier function and inflammatory disease
- Williams, BB; Tebbutt, NC; Buchert, M; Putoczki, TL; Doggett, K; Bao, S; Johnstone, CN; Masson, F; Hollande, F; Burgess, AW; Scott, AM; Ernst, M; Heath, JK;
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
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-06-15 09:53:31Last Modified: 2015-08-13 03:12:37