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.
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Quan
Q
Qiu
Ze
Z
Zheng
Lin
L
Chang
Yuan-Si
YS
Zhao
Can
C
Tan
Aditya
A
Dandekar
Zheng
Z
Zhang
Zhenghong
Z
Lin
Ming
M
Gui
Xiu
X
Li
Tongshuai
T
Zhang
Qingfei
Q
Kong
Hulun
H
Li
Sha
S
Chen
An
A
Chen
Randal J
RJ
Kaufman
Wei-Lei
WL
Yang
Hui-Kuan
HK
Lin
Donna
D
Zhang
Harris
H
Perlman
Edward
E
Thorp
Kezhong
K
Zhang
Deyu
D
Fang
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D016503:Drug Delivery Systems; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D047468:Immunoprecipitation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013582:Synovial Fluid / Q000166:cytology; D048029:TNF Receptor-Associated Factor 6 / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
D016207:Cytokines; D047428:Protein Kinase Inhibitors; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases