Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis
Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis
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DOI：
10.1172/jci32639
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Van den Berg, Wim B.
中科院分区：
文献类型：
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作者：
Abdollahi-Roodsaz, Shahla;Joosten, Leo A. B.;Van den Berg, Wim B.
TLR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而促进类风湿性关节炎的进展。在这里，我们表明，TLR 2和TLR 4，而不是TLR 9，参与了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的作用。我们使用IL-1受体拮抗剂敲除（IL 1 rn（-/-））小鼠研究了TLR 2、TLR 4和TLR 9在关节炎进展中的参与，这些小鼠自发地发展自身免疫性T细胞介导的关节炎。关节炎的自发发作依赖于微生物植物群激活TLR，因为无菌小鼠不会发生关节炎。IL 1 rn（-/-）Tlr 2（-/-）小鼠的临床和组织病理学评价显示更严重的关节炎，其特征在于Tcl 3的抑制功能降低和T细胞产生的IFN-γ显著增加。相比之下，IL 1 rn（-/-）Tlr 4（-/-）小鼠对严重关节炎有保护作用，并且Th 17细胞数量明显减少，产生IL-17的能力降低。缺乏Tlr 9并不影响关节炎的进展。虽然靶向TLR 2的任何治疗干预似乎仍然很复杂，但TLR 4在包括IL-17在内的许多致病性细胞因子上游的严格位置为类风湿性关节炎提供了一个有趣的潜在治疗靶点。
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.