Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis.
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.
Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. s.abdollahi-roodsaz@reuma.umcn.nl
Shahla
S
Abdollahi-Roodsaz
Leo A B
LA
Joosten
Marije I
MI
Koenders
Isabel
I
Devesa
Mieke F
MF
Roelofs
Timothy R D J
TR
Radstake
Marleen
M
Heuvelmans-Jacobs
Shizuo
S
Akira
Martin J H
MJ
Nicklin
Fátima
F
Ribeiro-Dias
Wim B
WB
van den Berg
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D005856:Germ-Free Life / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
D053590:Interleukin 1 Receptor Antagonist Protein; D020381:Interleukin-17; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9