Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis.
OBJECTIVE
Degeneration of extracellular matrix of cartilage leads to the production of molecules capable of activating the immune system via Toll-like receptor 4 (TLR-4). The objective of this study was to investigate the involvement of TLR-4 activation in the development and progression of autoimmune destructive arthritis.


METHODS
A naturally occurring TLR-4 antagonist, highly purified lipopolysaccharide (LPS) from Bartonella quintana, was first characterized using mouse macrophages and human dendritic cells (DCs). Mice with collagen-induced arthritis (CIA) and mice with spontaneous arthritis caused by interleukin-1 receptor antagonist (IL-1Ra) gene deficiency were treated with TLR-4 antagonist. The clinical score for joint inflammation, histologic characteristics of arthritis, and local expression of IL-1 in joints were evaluated after treatment.


RESULTS
The TLR-4 antagonist inhibited DC maturation induced by Escherichia coli LPS and cytokine production induced by both exogenous and endogenous TLR-4 ligands, while having no effect on these parameters by itself. Treatment of CIA using TLR-4 antagonist substantially suppressed both clinical and histologic characteristics of arthritis without influencing the adaptive anti-type II collagen immunity crucial for this model. Treatment with TLR-4 antagonist strongly reduced IL-1beta expression in articular chondrocytes and synovial tissue. Furthermore, such treatment inhibited IL-1-mediated autoimmune arthritis in IL-1Ra(-/-) mice and protected the mice against cartilage and bone pathology.


CONCLUSIONS
In the present study, we demonstrate for the first time that inhibition of TLR-4 suppresses the severity of experimental arthritis and results in lower IL-1 expression in arthritic joints. Our data suggest that TLR-4 might be a novel target in the treatment of rheumatoid arthritis.
Abdollahi-Roodsaz
Shahla
S
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. s.abdollahi-roodsaz@reuma.umcn.nl
Joosten
Leo A B
LA
Roelofs
Mieke F
MF
Radstake
Timothy R D J
TR
Matera
Giovanni
G
Popa
Calin
C
van der Meer
Jos W M
JW
Netea
Mihai G
MG
van den Berg
Wim B
WB
D000818:Animals; D001168:Arthritis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4