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

J Clin Invest. 2008 Jan;118(1):205-16. doi: 10.1172/JCI32639.


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-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / microbiology
  • Disease Models, Animal
  • Germ-Free Life / genetics
  • Germ-Free Life / immunology*
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / immunology
  • Interleukin-17 / immunology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • T-Lymphocytes, Regulatory / immunology*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / immunology


  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-17
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9