| First Author | Geesala R | Year | 2019 |
| Journal | J Leukoc Biol | Volume | 105 |
| Issue | 4 | Pages | 767-781 |
| PubMed ID | 30694569 | Mgi Jnum | J:273061 |
| Mgi Id | MGI:6284888 | Doi | 10.1002/JLB.4A0718-283RR |
| Citation | Geesala R, et al. (2019) Loss of RHBDF2 results in an early-onset spontaneous murine colitis. J Leukoc Biol 105(4):767-781 |
| abstractText | 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. |
