Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis
J. Clin. Invest. 118: 205-216 (2007). doi:10.1172/JCI32639.
Copyright ©2007 by the American Society for Clinical Investigation
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Shahla Abdollahi-Roodsaz1, Leo A.B. Joosten1, Marije I. Koenders1, Isabel Devesa1, Mieke F. Roelofs1, Timothy R.D.J. Radstake1, Marleen Heuvelmans-Jacobs1, Shizuo Akira2, Martin J.H. Nicklin3, Fátima Ribeiro-Dias4 and Wim B. van den Berg1
1Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
2Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
3University of Sheffield, Division of Genomic Medicine, Sir Henry Wellcome Laboratories for Medical Research, Sheffield, United Kingdom.
4Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil.
Address correspondence to: Shahla Abdollahi-Roodsaz, Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500HB, Nijmegen, The Netherlands. Phone: 00-31-24-3616451; Fax: 00-31-24-3540403; E-mail: s.abdollahi-roodsaz@reuma.umcn.nl.
Published January 2, 2008
Received for publication May 9, 2007, and accepted in revised form October 3, 2007.
Abstract
TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or host-derived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist–knockout (IL1rn–/–) mice, which spontaneously develop an autoimmune T cell–mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn–/–Tlr2–/– mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-? production by T cells. IL1rn–/–Tlr4–/– mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis. |
