Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

作者：Shahla Abdollahi‐Roodsaz, Leo A. B. Joosten, Mieke F. Roelofs, Timothy R. D. J. Radstake, Giovanni Matera, Călin D. Popa, Jos W. M. van der Meer, Mihai Gheorghe Netea, Wim B. van den Berg · 发表于：Arthritis & Rheumatism · 年份：2007 · DOI：10.1002/art.22848 · 被引用次数：304 · 研究领域：Immune Response and Inflammation、Bartonella species infections research、Inflammasome and immune disorders

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(-/-) mi...