Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17-dependent arthritis in mice
Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17-dependent arthritis in mice
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DOI：
10.1002/art.34328
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发表时间：
2012-06-01
影响因子：
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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;van de Loo, Fons A. J.;van den Berg, Wim B.
目的越来越多的证据表明Toll样受体（TLR）参与了关节炎的发生发展，然而由髓样分化因子88（MyD 88）和TRIF介导的TLRs信号通路在关节炎发生发展中的作用尚不清楚。本研究的目的是研究MyD 88和TRIF在慢性实验性关节炎和伴随的适应性免疫应答中的特定作用。方法在野生型、MyD 88-/-和Triflps 2（TRIF-/-）小鼠中通过反复关节内注射链球菌细胞壁（SCW）片段诱导慢性关节炎。在慢性关节炎期间分析SCW特异性T细胞和B细胞反应、关节肿胀和组织病理学变化。结果MyD 88和TRIF途径均参与抗原特异性T细胞增殖和抗体产生，其中MyD 88途径起主导作用。关节肿胀和滑膜炎症的严重程度，以及软骨和骨的组织病理学损伤，强烈依赖于MyD 88信号，而TRIF是多余的。MyD 88信号传导对于致病性T细胞应答的发展至关重要（即，白细胞介素-17 [IL-17]产生）。有趣的是，当T细胞依赖期延长时，TRIF信号似乎下调骨侵蚀，这种作用伴随着对IL-17产生的抑制作用。结论MyD 88在T细胞驱动性关节炎中起重要作用，TRIF具有反调节作用。这些发现为通路特异性干扰提供了理论基础，以阻断致病特征并保留或刺激TLR信号传导的有益方面。
Objective Increasing evidence indicates the involvement of Toll-like receptors (TLRs) in the progression of arthritis; however, the contribution of the two signaling pathways used by TLRs, which are mediated by myeloid differentiation factor 88 (MyD88) and TRIF, remains unclear. The objective of this study was to investigate the specific roles of MyD88 and TRIF in chronic experimental arthritis and the accompanying adaptive immune responses. Methods Chronic arthritis was induced in wild-type, MyD88-/-, and Triflps2 (TRIF-/-) mice by repetitive intraarticular injections of streptococcal cell wall (SCW) fragments. SCW-specific T cell and B cell responses, joint swelling, and histopathologic changes were analyzed during chronic arthritis. Results Both MyD88 and TRIF pathways contributed to antigen-specific T cell proliferation and antibody production, with the MyD88 pathway playing the dominant role. The severity of joint swelling and synovial inflammation, as well as the histopathologic damage to cartilage and bone, was strongly dependent on MyD88 signaling, whereas TRIF was redundant. MyD88 signaling was critical for the development of pathogenic T cell response (i.e., interleukin-17 [IL-17] production) in response to SCW antigen. Interestingly, when the T celldependent phase was prolonged, TRIF signaling appeared to down-regulate bone erosion, an effect accompanied by an inhibitory effect on IL-17 production. Conclusion This study reveals a central role of MyD88 and a counterregulatory function of TRIF in T celldriven arthritis. The findings provide a rationale for a pathway-specific interference in order to block the pathogenic features and to preserve or stimulate the beneficial aspects of TLR signaling.