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 1

Effect of microbial status of IL1rn–/– mice on the development of arthritis and cytokine response to TCR and TLR stimulations.

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Effect of microbial status of IL1rn–/– mice on the development of arthri...
The incidence (A) and severity (B) of arthritis are completely abolished in germ-free (GF) IL1rn–/– mice, and infection of GF mice with Lactobacillus (arrows) leads to the same disease expression as in non–germ-free (NGF) animals. Arthritis severity was scored on a scale from 0 to 2 for each paw; n ≥ 6 per group. (C and D) Splenic lymphocytes (2 × 105) were stimulated with plate-coated anti-CD3 (2 μg/ml), Pam3Cys (100 ng/ml), or LPS (200 ng/ml) for 72 hours. IL-1 (C) and IL-17 (D) were measured using Luminex multianalyte technology (see Methods). Data are expressed as mean ± SD and are representative of 2 independent experiments.