Shift From Toll-like Receptor 2 (TLR-2) Toward TLR-4 Dependency in the Erosive Stage of Chronic Streptococcal Cell Wall Arthritis Coincident With TLR-4-Mediated Interleukin-17 Production
Shift From Toll-like Receptor 2 (TLR-2) Toward TLR-4 Dependency in the Erosive Stage of Chronic Streptococcal Cell Wall Arthritis Coincident With TLR-4-Mediated Interleukin-17 Production
复制标题
DOI：
10.1002/art.24127
复制
发表时间：
2008-12-01
影响因子：
--
通讯作者：
van den Berg, Wim B.
中科院分区：
文献类型：
--
作者：
Abdollahi-Roodsaz, Shahla;Joosten, Leo A. B.;van den Berg, Wim B.
Objective. Toll样受体（TLR）可通过识别在关节炎关节中反复发现的微生物以及内源性配体来激活类风湿性关节炎（RA）中的先天性和适应性免疫应答。本研究的目的是探讨TLR-2和TLR-4在慢性破坏性链球菌细胞壁（SCW）诱导的关节炎的发展中的参与，其中白细胞介素-1（IL-1）/IL-17依赖性T细胞驱动的病理变化取代了巨噬细胞驱动的急性期。通过在野生型、TLR-2（-/-）和TLR-4（-/-）小鼠中4次重复关节内注射SCW片段诱导慢性SCW关节炎。对关节炎的临床、组织病理学和免疫学参数进行评价。急性期关节肿胀的TLR-2依赖性在慢性期转变为TLR-4依赖性。在TLR-4-/-小鼠中，模型后期的持续性关节炎症得到显著抑制。在慢性期，TLR-4积极促进基质金属蛋白酶（MMP）介导的软骨破坏和破骨细胞形成，因为MMP特异性聚集蛋白聚糖新表位VDIPEN和破骨细胞标志物组织蛋白酶K的表达在TLR-4（-/-）小鼠中显著降低。此外，TLR-4（-/-）小鼠表达较少的IL-1 β、肿瘤坏死因子α、IL-6和IL-23，这些细胞因子与IL-17的产生有关。因此，SCW特异性IL-17的产生依赖于TLR-4的激活，因为关节炎TLR-4（-/-）小鼠的T细胞在SCW刺激后产生的IL-17明显减少，而干扰素-γ的产生没有受到影响。这些数据表明TLR-4参与关节炎的慢性和糜烂特征，与抗原特异性IL-17应答一致。TLR-4在侵蚀性关节炎分级中的高位置为RA提供了一个有趣的治疗靶点。
Objective. Toll-like receptors (TLRs) may activate innate and adaptive immune responses in rheumatoid arthritis (RA) through recognition of microbial as well as endogenous ligands that have repeatedly been found in arthritic joints. The objective of this study was to investigate the involvement of TLR-2 and TLR-4 in the development of chronic destructive streptococcal cell wall (SCW)-induced arthritis, in which interleukin-1 (IL-1)/IL-17-dependent T cell-driven pathologic changes replace the macrophage-driven acute phase.Methods. Chronic SCW arthritis was induced by 4 repeated intraarticular injections of SCW fragments in wild-type, TLR-2(-/-), and TLR-4(-/-) mice. Clinical, histopathologic, and immunologic parameters of arthritis were evaluated.Results. The TLR-2 dependency of joint swelling during the acute phase was shifted to TLR-4 dependency during the chronic phase. Persistent joint inflammation in the latter phase of the model was significantly suppressed in TLR-4-/- mice. In the chronic phase, TLR-4 actively contributed to matrix metalloproteinase (MMP)-mediated cartilage destruction and to osteoclast formation, since the expression of the MMP-specific aggrecan neoepitope VDIPEN and the osteoclast marker cathepsin K was significantly reduced in TLR-4(-/-) mice. Furthermore, TLR-4(-/-) mice expressed less IL-1 beta, tumor necrosis factor alpha, IL-6, and IL-23, cytokines that are implicated in IL-17 production. Accordingly, SCW-specific IL-17 production was found to be dependent on TLR-4 activation, since T cells from arthritic TLR-4(-/-) mice produced markedly less IL-17 upon SCW stimulation, whereas interferon-gamma production remained unaffected.Conclusion. These data indicate the involvement of TLR-4 in the chronicity and erosive character of arthritis coincident with the antigen-specific IL-17 response. The high position of TLR-4 in the hierarchy of erosive arthritis provides an interesting therapeutic target for RA.