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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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 6

Decreased IL-17 in IL1rn–/–Tlr4–/– mice and IL-1–mediated effects of TLR4 activation on IL-23/IL-17 production.

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Decreased IL-17 in IL1rn–/–Tlr4–/– mice and IL-1–mediated effects of TLR...
(A–D and F) Spleens and lymph nodes from 5- to 6-week-old mice without arthritis were isolated and disrupted. CD3+ T lymphocytes were isolated using magnetic beads (MACS). (A and B) Th17 FACS analysis following stimulation with PMA (50 ng/ml), ionomycin (1 μg/ml), and brefeldin (1 μl/ml) for 5 hours ; n = 4. (C) IL-17 production by splenic and lymph node T cells upon stimulation with anti-CD3 (0.5 μg/0.2 ml/well) and anti-CD28 (2 μg/ml) for 72 hours; measured by Luminex; n ≥ 6. (D) TLR4 activation of bone marrow–derived DCs by 100 ng/ml LPS for 24 hours resulted in higher IL-23 production in IL1rn–/– cells compared with BALB/c WT. IL-23 was measured by ELISA; n = 10. (E) TLR4 (200 ng/ml LPS) plus anti-CD3 (1 μg/ml) activation of splenic T cells leads to higher IL-1–mediated IL-17 production in IL1rn–/– cells compared with WT cells, as measured by Luminex; n = 5. (F) Bone marrow–derived DCs from IL1rn–/–Tlr4–/– mice are not compromised in IL-23 production upon non-TLR4 stimulations. DCs were stimulated with 100 ng/ml LPS, 100 ng/ml Pam3Cys, or a cocktail of IL-1β (25 ng/ml), TNF-α (25 ng/ml), IL-6 (100 ng/ml), and PGE2 (1 μg/ml) for 24 hours; n = 4 per group. Data are mean ± SEM. NRS, normal rabbit serum. *P < 0.05, **P < 0.01, and ***P < 0.001.