Loss of RHBDF2 results in an early-onset spontaneous murine colitis

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.

The complex life of rhomboid pseudoproteases

“…EGFR signaling, which requires the cleavage and release of its cognate EGFR ligands by ADAM17/TACE, promotes epithelial repair, and maintains mucosal and skin barrier integrity [109]. A deregulated barrier function results in bacterial translocation and inflammation, and is seen as an important contributor to inflammatory disorders such asthma and colitis [110], and to a common side effect associated with EGFR inhibition in cancer patients, an inflammatory skin rash, accompanied by increased susceptibility to Staphylococcus aureus infections [74]. In contrast to ADAM17/TACE deficiency, iRhom1 or iRhom2 KO mice have no barrier defects at homeostasis, presumably due to redundant roles of iRhom1 and iRhom2 in the regulation of pathways that control epithelial regeneration and integrity [110].…”

iRhom2: An Emerging Adaptor Regulating Immunity and Disease

“…The same mice conversely are protected from LPS induced septic shock [ 44 ], rheumatoid arthritis [ 61 , 92 ], hemophilic arthropathy [ 93 ], lupus nephritis [ 64 ], post intestinal ischaemia reperfusion acute lung injury [ 94 ], renal injury from particulate matter [ 95 ] and inflammatory bowel disease [ 96 ], all of which are TNFα mediated with the exception of lupus nephritis which is TNFα and HB-EGF mediated [ 64 ]. A previous study shows the iRhom2 null mice being more susceptible to inflammatory bowel disease using a spontaneous colitis mouse model relating it to altered T helper cell cytokine production [ 97 ].…”

Novel functions of inactive rhomboid proteins in immunity and disease

“…iRhom1 and iRhom2‐dependent ADAM17/EGFR signaling plays a pivotal role in promoting epithelial cell repair and in maintaining mucosal and skin barrier integrity (Fig. C) . Lack of either ADAM17 or EGFR in keratinocytes leads to profound defects in epidermal barrier integrity over time resulting in chronic dermatitis .…”

“…In contrast to Adam17 deficiency in mice, iRhom1 or iRhom2 ‐deficient mice have no barrier defects at homeostasis, presumably due to redundant or compensatory functions of iRhom1 and iRhom2 in the epithelium that allows for intact ADAM17 activity . However, their contributions to repair during injury and inflammation remained unclear.…”

“…However, their contributions to repair during injury and inflammation remained unclear. We therefore recently explored the role of iRhom2 in both DSS‐colitis and in the non‐injury Il10 ‐deficient mouse model of spontaneous colitis . Loss of iRhom2 in Il10 ‐deficient mice results in an earlier onset and increased severity of colitis that is associated with early colonization by potentially pathogenic bacteria of the Enterobacteriaceae family.…”