iRHOM2 is a critical pathogenic mediator of inflammatory arthritis

Abstract

iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-α convertase (TACE), which controls shedding of TNF-α and its biological activity in vivo. TACE is a potential target to treat TNF-α-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-α in Rhbdf2-deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/ TACE-dependent shedding of TNF-α in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells.

iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

“…5 I and J) and insensitive to the ADAM17 inhibitor SP26 (Fig. 5K), providing additional evidence that substrate trafficking, and the function of the related ADAM10, is normal in iRhom2 −/− mEFs and in iRhom2 −/− mEFs treated with iRhom1 siRNA (7).…”

“…Inactivation of ADAM17 in myeloid cells protects from endotoxin shock and from inflammatory arthritis, both of which depend on the release of soluble TNFα from myeloid cells (6,7). Moreover, mice lacking ADAM17 resemble mice lacking the EGFR in that they have open eyes at birth, skin barrier defects, enlarged heart valves, abnormal mammary ductal morphogenesis, and lung defects (3,(8)(9)(10)(11).…”

“…ADAM17 is also responsible for the proteolytic release, or "ectodomain shedding" of a variety of other membrane proteins from the cell surface, such as Kit ligand (KitL) 1 and 2 (12), the vascular endothelial growth factor receptor 2 and many others (13,14). However, most phenotypes caused by inactivation of ADAM17 can be explained through loss of shedding of TNFα or of EGFR ligands (3,(6)(7)(8)(9)(10)(11), so these can be considered the functionally dominant substrates of ADAM17.…”

“…Recently, the inactive Rhomboid iRhom2, a catalytically inactive member of the Rhomboid family of intramembrane proteinases (19)(20)(21)(22), was identified as a crucial regulator of the maturation of ADAM17 in hematopoietic cells. Interestingly, mature ADAM17 is present in several tissues and cell types of iRhom2 −/− mice, including mouse embryonic fibroblasts (mEFs) and keratinocytes (7,23). This raises questions about whether iRhom2 affects the function of ADAM17 in cells outside of immune cells.…”

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…Similar to ADAM17 KO mice, mice deficient for iRhom2 are defective in TNF release from myeloid cells. iRhom2 KO mice respond less severely to sepsis, are protected from experimental arthritis, but exhibit increased sensitivity to Listeria infection, hallmarks of TNF biology [12, [22][23][24]. iRhom redundancy is illustrated by the fact that iRhom single KO mouse embryonic fibroblasts retain substantial ADAM17 activity, whereas ADAM17 is inactive in double knockout (DKO) cells [20,21].…”