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

doi:10.1172/JCI66168

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iRHOM2 is a critical pathogenic mediator of inflammatory arthritis

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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, …

The Journal of clinical investigation, Vol.123(2), pp.928-932

02/01/2013

DOI: 10.1172/JCI66168

PMCID: PMC3561822

PMID: 23348744

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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.

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Title: Subtitle: iRHOM2 is a critical pathogenic mediator of inflammatory arthritis
Creators: Priya Darshinee A Issuree - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Thorsten Maretzky - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
David R McIlwain - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Sébastien Monette - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Xiaoping Qing - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Philipp A Lang - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Steven L Swendeman - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Kyung-Hyun Park-Min - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Nikolaus Binder - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
George D Kalliolias - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Anna Yarilina - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Keisuke Horiuchi - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Lionel B Ivashkiv - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Tak W Mak - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Jane E Salmon - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Carl P Blobel - Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, and
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.123(2), pp.928-932
DOI: 10.1172/JCI66168
PMID: 23348744
PMCID: PMC3561822
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 02/01/2013
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094388702771

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