iRHOM2 is a critical pathogenic mediator of inflammatory arthritis

Jane Salmon, Carl Blobel, Priya Darshinee Issuree, and Thorsten Maretzky of the Weill Cornell University Hospital for Special Surgery discuss the role of iRHOM2 in inflammatory arthritis. Highlights:

  • TNF-α has been implicated in the pathology of rheumatoid arthritis (RA) and other inflammatory diseases. RA patients are currently treated with TNF inhibitors, but these therapeutics have many deleterious side effects.
  • iRHOM2 regulates the maturation of TACE, and enzyme that cleaves and releases TNF-α from the surface of myeloid cells that mediate inflammation during arthritis.
  • Inactivation of the gene that encodes iRHOM2 (Rhbdf2) protects mice from inflammatory arthritis.
  • These findings suggest that iRHOM2 could be a suitable therapeutic target for the treatment of RA.

Published January 25, 2013, by The JCI

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iRHOM2 is a critical pathogenic mediator of inflammatory arthritis
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
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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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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