Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis
Shahla Abdollahi-Roodsaz, Leo A.B. Joosten, Marije I. Koenders, Isabel Devesa, Mieke F. Roelofs, Timothy R.D.J. Radstake, Marleen Heuvelmans-Jacobs, Shizuo Akira, Martin J.H. Nicklin, Fátima Ribeiro-Dias, Wim B. van den Berg
Shahla Abdollahi-Roodsaz, Leo A.B. Joosten, Marije I. Koenders, Isabel Devesa, Mieke F. Roelofs, Timothy R.D.J. Radstake, Marleen Heuvelmans-Jacobs, Shizuo Akira, Martin J.H. Nicklin, Fátima Ribeiro-Dias, Wim B. van den Berg
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Research Article Autoimmunity

Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis

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-γ 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.

Authors

Shahla Abdollahi-Roodsaz, Leo A.B. Joosten, Marije I. Koenders, Isabel Devesa, Mieke F. Roelofs, Timothy R.D.J. Radstake, Marleen Heuvelmans-Jacobs, Shizuo Akira, Martin J.H. Nicklin, Fátima Ribeiro-Dias, Wim B. van den Berg

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Figure 7

TLR4-mediated stimulation of cytokine production by rheumatoid synovial fluid and in synovial biopsies of RA patients.

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TLR4-mediated stimulation of cytokine production by rheumatoid synovial ...
(A) HEK293-TLR4 cells were stimulated with PMA, IL-1β, TNF-α, and various TLR ligands as indicated in Methods. Mean IL-8 concentrations (Luminex assay) of triplicates are shown. (B) HEK293 and HEK293-TLR4 cells were stimulated with synovial fluid of RA patients in the presence of a TNF-α blocker (Enbrel; 100 ng/ml) or remained unstimulated (medium control). IL-8 was measured in culture supernatants after 24 hours. Stimulation index over medium control of each cell line is shown on the y axis; n = 7. Data are mean ± SEM. ***P < 0.001. (C) Synovial biopsies of RA patients were cultured ex vivo with or without TLR4 antagonist (10 μg/ml) for 24 hours. Experiments were performed in triplicate. The concentration of cytokines was measured using Luminex. Data are mean ± SEM from 7 RA patients.