Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis

Quan Qiu, Ze Zheng, Lin Chang, Yuan Si Zhao, Can Tan, Aditya Dandekar, Zheng Zhang, Zhenghong Lin, Ming Gui, Xiu Li, Tongshuai Zhang, Qingfei Kong, Hulun Li, Sha Chen, An Chen, Randal J. Kaufman, Wei Lei Yang, Hui Kuan Lin, Donna Zhang, Harris PerlmanEdward Thorp, Kezhong Zhang, Deyu Fang

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

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 IRE1α 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 IRE1α-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.

Original languageEnglish (US)
Pages (from-to)2477-2490
Number of pages14
JournalEMBO Journal
Volume32
Issue number18
DOIs
StatePublished - Sep 11 2013

Keywords

  • IRE1
  • Inflammation
  • TRAF6
  • Ubiquitination

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Qiu, Q., Zheng, Z., Chang, L., Zhao, Y. S., Tan, C., Dandekar, A., Zhang, Z., Lin, Z., Gui, M., Li, X., Zhang, T., Kong, Q., Li, H., Chen, S., Chen, A., Kaufman, R. J., Yang, W. L., Lin, H. K., Zhang, D., ... Fang, D. (2013). Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO Journal, 32(18), 2477-2490. https://doi.org/10.1038/emboj.2013.183