Loss of RHBDF2 results in an early-onset spontaneous murine colitis
Autor: | Prajwal Gurung, Joseph Skurski, Thorsten Maretzky, Priya D. Issuree, Garima Dixit, David E. Elliott, Willow Schanz, Mikayla Biggs, David K. Meyerholz, Ramasatyaveni Geesala |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cell Membrane Permeability Colon Immunology RHBDF2 Biology Gut flora Inflammatory bowel disease Article Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Immunology and Allergy Interferon gamma Colitis Ulcer Tumor Necrosis Factor-alpha Dextran Sulfate Epithelial Cells Cell Biology Th1 Cells medicine.disease biology.organism_classification Ulcerative colitis Gastrointestinal Microbiome Interleukin-10 Up-Regulation Interleukin 10 030104 developmental biology Solubility 030220 oncology & carcinogenesis Disease Progression Cytokines Carrier Proteins medicine.drug |
Zdroj: | Journal of Leukocyte Biology. 105:767-781 |
ISSN: | 1938-3673 0741-5400 |
Popis: | Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation-mediated pathologies that include Crohn’s disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane-bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10−/−/Rhbdf2−/− mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10−/−/Rhbdf2−/− mice correlated with a dysbiotic gut microbiota and elevated Th1-associated immune responses with increased interferon gamma and IL2 production. In addition, Il10−/−/Rhbdf2−/− mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2−/− mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium-induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD. |
Databáze: | OpenAIRE |
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