Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis
Shahla Abdollahi-Roodsaz, … , Fátima Ribeiro-Dias, Wim B. van den Berg
Shahla Abdollahi-Roodsaz, … , Fátima Ribeiro-Dias, Wim B. van den Berg
Published December 3, 2007
Citation Information: J Clin Invest. 2008;118(1):205-216. https://doi.org/10.1172/JCI32639.
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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 4

Influence of Tlr2 deficiency on various Th cell subsets and the expression of related cytokines.

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Influence of Tlr2 deficiency on various Th cell subsets and the expressi...
mRNA expression of T cell markers in inflamed synovium of the ankle joints (A) and spleens (B) of IL1rn–/–Tlr2–/– compared with IL1rn–/–Tlr2+/+ mice. Synovial biopsies were pooled from more than 5 joints of 15-week-old mice, and spleens were from 4 nonarthritic 6-week-old mice. mRNA expression was measured by quantitative PCR. Relative mRNA expression compared with the housekeeping gene GAPDH (2-dCt × 1,000) is shown on the y axis. IFN-γ (C) and IL-17 (D) production by spleen and lymph node cells upon 72 hours stimulation with anti-CD3 (0.5 μg/0.2 ml/well) and anti-CD28 (2 μg/ml), measured by Luminex; results are mean ± SEM from a representative experiment with n > 4 mice per group. Protein expression of Foxp3 (E) and CD25 (F) on CD4+-gated CD25+Foxp3+ cells from whole blood and spleen of 15-week-old mice after correction for isotype-matched IgG control; mean ± SEM of n = 3 from a representative experiment. (G and H) T cell suppression assay on splenic cells of IL1rn–/–Tlr2+/+ and IL1rn–/–Tlr2–/– mice. (G) CD4+CD25– Teffs (50,000 cells/well) were stimulated with 1 μg/ml anti-CD3, 2 μg/ml concanavalin A, or 60 IU/ml IL-6 (negative control) in the presence of 50,000/well irradiated CD4– cells as APCs. After 3 days, proliferation was measured by [3H]thymidine incorporation. (H) For suppression assays, cells were incubated with anti-CD3 and APCs in the presence of titrated numbers of Tregs (CD4+CD25+). Percent suppression was calculated relative to the cultures without Tregs. Measurements were performed in triplicate, and values shown are mean ± SEM of 4 mice per group. mRNA expression of TGF-β1 in noninflamed and inflamed ankle synovium (I) and spleen (J), measured by quantitative PCR. Relative mRNA expression compared with GAPDH is shown. *P < 0.05.