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

Abstract

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.

• Authors: Shahla Abdollahi-Roodsaz, Leo A B Joosten, Mieke F Roelofs, Timothy R D J Radstake, Giovanni Matera, Calin Popa, Jos W M van der Meer, Mihai G Netea, Wim B van den Berg
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 56 Issue 9 Pg. 2957-67 (Sep 2007) ISSN: 0004-3591 [Print] United States
• PMID: 17763416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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