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Toll‐like receptor‐mediated IRE1α activation as a therapeutic target for inflammatory arthritis
Author(s) -
Qiu Quan,
Zheng Ze,
Chang Lin,
Zhao YuanSi,
Tan Can,
Dandekar Aditya,
Zhang Zheng,
Lin Zhenghong,
Gui Ming,
Li Xiu,
Zhang Tongshuai,
Kong Qingfei,
Li Hulun,
Chen Sha,
Chen An,
Kaufman Randal J,
Yang WeiLei,
Lin HuiKuan,
Zhang Donna,
Perlman Harris,
Thorp Edward,
Zhang Kezhong,
Fang Deyu
Publication year - 2013
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2013.183
Subject(s) - inflammation , biology , cytokine , immunology , arthritis , cancer research , inflammatory arthritis , proinflammatory cytokine , tumor necrosis factor alpha , toll like receptor , innate immune system , immune system
In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll‐like receptor (TLR)‐mediated signalling during RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol‐requiring enzyme 1α (IRE1α), a primary unfolded protein response (UPR) transducer. Myeloid‐specific deletion of the IRE1 α gene protected mice from inflammatory arthritis, and treatment with the IRE1α‐specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1α was required for optimal production of pro‐inflammatory cytokines as evidenced by impaired TLR‐induced cytokine production in IRE1 α‐null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor‐associated factor 6 (TRAF6) plays a key role in TLR‐mediated IRE1α activation by catalysing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1α phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6‐mediated IRE1α ubiquitination in regulating TLR‐induced IRE1α activation in pro‐inflammatory cytokine production, and demonstrated that IRE1α is a potential therapeutic target for inflammatory arthritis.