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

EMBO J. 2013 Sep 11;32(18):2477-90. doi: 10.1038/emboj.2013.183. Epub 2013 Aug 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Blotting, Western
  • Cell Line
  • Cytokines / metabolism*
  • Drug Delivery Systems
  • Endoribonucleases / antagonists & inhibitors
  • Endoribonucleases / metabolism*
  • Enzyme Activation / physiology*
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling
  • Immunoprecipitation
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Synovial Fluid / cytology
  • TNF Receptor-Associated Factor 6 / pharmacology
  • Toll-Like Receptors / metabolism*
  • Unfolded Protein Response / physiology*


  • Cytokines
  • Protein Kinase Inhibitors
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases