iRHOM2 is a critical pathogenic mediator of inflammatory arthritis
Priya Darshinee A. Issuree, … , Jane E. Salmon, Carl P. Blobel
Priya Darshinee A. Issuree, … , Jane E. Salmon, Carl P. Blobel
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):928-932. https://doi.org/10.1172/JCI66168.
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Brief Report

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.

Authors

Priya Darshinee A. Issuree, Thorsten Maretzky, David R. McIlwain, Sébastien Monette, Xiaoping Qing, Philipp A. Lang, Steven L. Swendeman, Kyung-Hyun Park-Min, Nikolaus Binder, George D. Kalliolias, Anna Yarilina, Keisuke Horiuchi, Lionel B. Ivashkiv, Tak W. Mak, Jane E. Salmon, Carl P. Blobel

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Figure 3

Complement C5a and ICs activate TACE to shed TNF-α.

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Complement C5a and ICs activate TACE to shed TNF-α. (A) C5a-induced TNF-...
(A) C5a-induced TNF-α shedding from TaceΔMC BMDMs or fetal liver-derived macrophages from Tace–/– mice or controls, assessed by ELISA after 3 to 4 hours of stimulation (n = 4; mean + SD). (B) TNF-α shedding by human monocytes during 2-hour stimulation with C5a (1 μg/ml) plus TACE inhibitors (SP26, DPC333) and anti-TACE antibody D1(A12) (representative of 4 experiments; mean + SD; *P < 0.05). (C) TNF-α shedding by human monocytes induced by FcγR crosslinking (mAbs or model IC [concentration, 0.25 mg/ml IVIg]) and/or C5a (1 μg/ml), assessed after 2 hours (representative of 3 experiments; mean + SD, *P < 0.05, DPC333 vs. control). (D) Human monocytes have reduced RHBDF2 mRNA when treated with iRHOM2 siRNA, but not with TACE siRNA, and (E) iRHOM2 siRNA treatment of human monocytes reduced mature TACE, but not pro-TACE, in a Western blot, whereas TACE siRNA reduced pro- and mature TACE (n = 3). (F) TNF-α release from C5a-, IC-, and IC/C5a-stimulated cells treated with or without iRHOM2 siRNA or TACE siRNA (n = 3; mean + SD; *P < 0.05, stimulated control siRNA vs. iRHOM2 siRNA or TACE siRNA, 1-way ANOVA, followed by Dunnett’s test). (G) Soluble TNF-α in the peritoneal lavage of TaceΔMC (n = 6) or Rhbdf2–/– mice (n = 4) and controls injected with ova plus anti-ova for 3 to 4 hours (n = 6).