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

• DOI: 10.1038/emboj.2013.183
• Publication Date: 2013-08-13T14:03:35Z
• Authors: 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 Perlman; Edward Thorp; Kezhong Zhang; Deyu Fang
• Keywords: 0301 basic medicine; Blotting, Western; Enzyme-Linked Immunosorbent Assay; IRE1; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Cell Line; Arthritis, Rheumatoid; Mice; 03 medical and health sciences; Drug Delivery Systems; Health Sciences; Endoribonucleases; Synovial Fluid; Animals; Immunoprecipitation; Cellular and Developmental Biology; Phosphorylation; Protein Kinase Inhibitors; Inflammation; TNF Receptor-Associated Factor 6; Gene Expression Profiling; Macrophages; Toll-Like Receptors; Ubiquitination; Molecular; 3. Good health; Enzyme Activation; Cytokines; TRAF6

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.