Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

Arthritis Rheum. 2007 Sep;56(9):2957-67. doi: 10.1002/art.22848.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / blood
  • Arthritis / drug therapy*
  • Arthritis / immunology*
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / immunology*
  • Escherichia coli*
  • Lipopolysaccharides / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Toll-Like Receptor 4 / antagonists & inhibitors*


  • Lipopolysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4