Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: Critical role of myeloid differentiation factor 88
Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: Critical role of myeloid differentiation factor 88
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DOI：
10.4049/jimmunol.171.11.6145
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
van den Berg, WB
中科院分区：
文献类型：
--
作者：
Joosten, LAB;Koenders, MI;van den Berg, WB
IL-1 R/Toll样受体（TLR）超家族在先天免疫和炎症中起关键作用。在这项研究中，我们报告说，链球菌细胞壁（SCW）诱导的关节炎症主要是依赖于TLR-2信号，因为TLR-2缺陷的小鼠不能开发关节肿胀或抑制软骨基质合成。髓样分化因子88（MyD 88）是一种含有Toll/IL-1 R结构域的衔接分子，已知在IL-1 R/IL-18 R和TLR信号传导中具有中心作用。缺乏MyD 88的小鼠没有发生SCW诱导的关节炎;关节肿胀和软骨软骨细胞合成代谢功能的紊乱都完全消除。在MyD 88缺陷小鼠中，滑膜组织冲洗中促炎细胞因子和趋化因子的局部水平显著降低。组织学证实了MyD 88在急性关节炎症中的关键作用。TLR-2缺陷小鼠仍然允许炎性细胞流入关节腔，尽管细胞数量显著减少。在MyD 88缺陷小鼠的关节中没有观察到炎性细胞的流入。此外，MyD 88敲除小鼠中完全不存在软骨基质蛋白聚糖损失。这些发现清楚地表明，MyD 88是SCW诱导的关节炎症的关键组分。由于Toll样通路的激动剂大量参与脓毒性和类风湿性关节炎，靶向MyD 88可能是炎性关节疾病的新疗法。
The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either joint swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MyD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MyD88 did not develop SCW-induced arthritis; both joint swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MyD88-deficient mice. Histology confirmed the pivotal role of MyD88 in acute joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in joints of MyD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MyD88 knockout mice. These findings clearly demonstrated that MyD88 is a key component in SCW-induced joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MyD88 may be a novel therapy in inflammatory joint diseases.