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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 Article has an altmetric score of 7

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

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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 3

Higher severity and increased histopathology of IL1rn–/– arthritis caused by Tlr2 deficiency.

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Higher severity and increased histopathology of IL1rn–/– arthritis cause...
Percentage incidence (A) and severity score (B) of arthritis in IL1rn–/–Tlr2+/+ mice compared with IL1rn–/–Tlr2–/– littermates. Severity was scored macroscopically on a scale of 0–2 for each paw; n > 20 mice per group. (C) Histological assessment of the ankle joints at 15 weeks (mean ± SEM) on a scale between 0 and 3 for each parameter; n = 14 mice per group. (D) Representative histological images of ankle joints. Cell influx and chondrocyte death were scored on H&E-stained (top row), and cartilage and bone damage (arrows) were scored on safranin O–stained (bottom row) tissue sections. PG depletion is apparent from loss of red staining. Original magnification, ×50 for H&E and ×100 for safranin O staining. B, bone; C, cartilage; JS, joint space; S, synovium. *P < 0.05 and **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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