Abdollahi-Roodsaz Shahla, Joosten Leo A B, Koenders Marije I, Devesa Isabel, Roelofs Mieke F, Radstake Timothy R D J, Heuvelmans-Jacobs Marleen, Akira Shizuo, Nicklin Martin J H, Ribeiro-Dias Fátima, van den Berg Wim B
Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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.
Toll样受体（TLRs）可能通过识别关节炎关节中发现的微生物或宿主来源的配体，促进类风湿性关节炎的发展。在此，我们表明TLR2和TLR4而非TLR9参与自身免疫性关节炎的发病机制，并在T细胞和细胞因子的调节中发挥不同作用。我们使用白细胞介素-1受体拮抗剂敲除（IL1rn-/-）小鼠研究了TLR2、TLR4和TLR9在关节炎发展中的作用，这些小鼠会自发发展出自身免疫性T细胞介导的关节炎。关节炎的自发发作依赖于微生物菌群对TLR的激活，因为无菌小鼠不会发展为关节炎。对IL1rn-/-Tlr2-/-小鼠的临床和组织病理学评估显示关节炎更为严重，其特征是调节性T细胞（Tregs）的抑制功能降低，T细胞产生的干扰素-γ大幅增加。相比之下，IL1rn-/-Tlr4-/-小鼠对严重关节炎具有抵抗力，其辅助性T细胞17（Th17）细胞数量明显减少，产生白细胞介素-17的能力降低。缺乏Tlr9并不影响关节炎的发展。虽然任何针对TLR2的治疗干预似乎仍然很复杂，但TLR4在包括白细胞介素-17在内的多种致病细胞因子上游的关键地位，为类风湿性关节炎提供了一个有趣的潜在治疗靶点。
