iRHOM2 is a critical pathogenic mediator of infammatory 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)928-932
Number of pages5
JournalJournal of Clinical Investigation
Volume123
Issue number2
DOIs
Publication statusPublished - 2013 Feb 1

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Arthritis
Myeloid Cells
Complement C5a
Antigen-Antibody Complex
Rheumatoid Arthritis
Ligands
Skin
Genes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Issuree, P. D. A., Maretzky, T., McIlwain, D. R., Monette, S., Qing, X., Lang, P. A., ... Blobel, C. P. (2013). iRHOM2 is a critical pathogenic mediator of infammatory arthritis. Journal of Clinical Investigation, 123(2), 928-932. https://doi.org/10.1172/JCI66168

iRHOM2 is a critical pathogenic mediator of infammatory arthritis. / Issuree, Priya Darshinee A; Maretzky, Thorsten; McIlwain, David R.; Monette, Sébastien; Qing, Xiaoping; Lang, Philipp A.; Swendeman, Steven L.; Park-Min, Kyung Hyun; Binder, Nikolaus; Kalliolias, George D.; Yarilina, Anna; Horiuchi, Keisuke; Ivashkiv, Lionel B.; Mak, Tak W.; Salmon, Jane E.; Blobel, Carl P.

In: Journal of Clinical Investigation, Vol. 123, No. 2, 01.02.2013, p. 928-932.

Research output: Contribution to journalArticle

Issuree, PDA, Maretzky, T, McIlwain, DR, Monette, S, Qing, X, Lang, PA, Swendeman, SL, Park-Min, KH, Binder, N, Kalliolias, GD, Yarilina, A, Horiuchi, K, Ivashkiv, LB, Mak, TW, Salmon, JE & Blobel, CP 2013, 'iRHOM2 is a critical pathogenic mediator of infammatory arthritis', Journal of Clinical Investigation, vol. 123, no. 2, pp. 928-932. https://doi.org/10.1172/JCI66168
Issuree PDA, Maretzky T, McIlwain DR, Monette S, Qing X, Lang PA et al. iRHOM2 is a critical pathogenic mediator of infammatory arthritis. Journal of Clinical Investigation. 2013 Feb 1;123(2):928-932. https://doi.org/10.1172/JCI66168
Issuree, Priya Darshinee A ; Maretzky, Thorsten ; McIlwain, David R. ; Monette, Sébastien ; Qing, Xiaoping ; Lang, Philipp A. ; Swendeman, Steven L. ; Park-Min, Kyung Hyun ; Binder, Nikolaus ; Kalliolias, George D. ; Yarilina, Anna ; Horiuchi, Keisuke ; Ivashkiv, Lionel B. ; Mak, Tak W. ; Salmon, Jane E. ; Blobel, Carl P. / iRHOM2 is a critical pathogenic mediator of infammatory arthritis. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 2. pp. 928-932.
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AU - Kalliolias, George D.

AU - Yarilina, Anna

AU - Horiuchi, Keisuke

AU - Ivashkiv, Lionel B.

AU - Mak, Tak W.

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