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

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.
Mesh Terms:
Animals, Arthritis, Rheumatoid, Blotting, Western, Cell Line, Cytokines, Drug Delivery Systems, Endoribonucleases, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Gene Expression Profiling, Immunoprecipitation, Macrophages, Mice, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, Synovial Fluid, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Unfolded Protein Response
EMBO J.
Date: Sep. 11, 2013
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