Journal article
Loss of RHBDF2 results in an early-onset spontaneous murine colitis
Journal of leukocyte biology, Vol.105(4), pp.767-781
04/2019
DOI: 10.1002/JLB.4A0718-283RR
PMCID: PMC6585405
PMID: 30694569
Abstract
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.
Details
- Title: Subtitle
- Loss of RHBDF2 results in an early-onset spontaneous murine colitis
- Creators
- Ramasatyaveni Geesala - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USAWillow Schanz - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USAMikayla Biggs - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USAGarima Dixit - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USAJoseph Skurski - Immunology Graduate Program, Iowa City, Iowa, USAPrajwal Gurung - Immunology Graduate Program, Iowa City, Iowa, USADavid K Meyerholz - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USADavid Elliott - Department of Veterans Affairs Medical Center, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAPriya D Issuree - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USAThorsten Maretzky - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Journal of leukocyte biology, Vol.105(4), pp.767-781
- DOI
- 10.1002/JLB.4A0718-283RR
- PMID
- 30694569
- PMCID
- PMC6585405
- ISSN
- 0741-5400
- eISSN
- 1938-3673
- Grant note
- P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Infectious Diseases; Gastroenterology and Hepatology; Pathology; Biology; Internal Medicine
- Record Identifier
- 9984083875002771
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