| First Author | Qiu Q | Year | 2013 |
| Journal | EMBO J | Volume | 32 |
| Issue | 18 | Pages | 2477-90 |
| PubMed ID | 23942232 | Mgi Jnum | J:201886 |
| Mgi Id | MGI:5516130 | Doi | 10.1038/emboj.2013.183 |
| Citation | Qiu Q, et al. (2013) Toll-like receptor-mediated IRE1alpha activation as a therapeutic target for inflammatory arthritis. EMBO J 32(18):2477-90 |
| abstractText | 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 1alpha (IRE1alpha), a primary unfolded protein response (UPR) transducer. Myeloid-specific deletion of the IRE1alpha gene protected mice from inflammatory arthritis, and treatment with the IRE1alpha-specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1alpha was required for optimal production of pro-inflammatory cytokines as evidenced by impaired TLR-induced cytokine production in IRE1alpha-null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a key role in TLR-mediated IRE1alpha activation by catalysing IRE1alpha ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1alpha phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6-mediated IRE1alpha ubiquitination in regulating TLR-induced IRE1alpha activation in pro-inflammatory cytokine production, and demonstrated that IRE1alpha is a potential therapeutic target for inflammatory arthritis. |
