Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation
Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation
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DOI：
10.2353/ajpath.2009.090262
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发表时间：
2009-11-01
影响因子：
6
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.
Toll样受体可能通过识别炎症或细胞外基质变性产生的内源性配体参与慢性炎症性破坏性疾病的发病。据报道，类风湿关节中存在内源性TLR激动剂。在这项研究中，我们研究了局部产生的内源性配体激活TLR2和TLR4在关节炎症和破坏严重程度中的意义。通过腺病毒基因转移在幼鼠关节中过表达IL-1和肿瘤坏死因子，诱导非全身免疫激活的局部关节病理改变。在这里，我们报告了在一定剂量下，IL-1引起的局部关节炎症、软骨蛋白多糖耗竭和骨侵蚀依赖于TLR4的激活，而TLR2的激活没有明显的参与。相比之下，肿瘤坏死因子a驱动的关节病理似乎较少依赖TLR2和TLR4。在TLR4(-/-)小鼠中，IL-1诱导的骨质侵蚀和不可逆软骨破坏的严重程度显著减轻，尽管炎症程度相似，表明过程是不耦合的。此外，IL-1β诱导破骨细胞活性标志物组织蛋白酶K的表达依赖于TLR4。IL-1β在关节中的过度表达以及在体外对膝盖骨的IL-1刺激可以刺激内源性TLR4激动剂的释放，从而能够诱导TLR4介导的细胞因子的产生。这些数据强调了TLR4激活在类风湿性关节炎中的潜在相关性，特别是与IL-1介导的关节病理有关。(Am J Pathol 20091752004年-2013年；DOI：10.2353/ajpath.2009.090262)
Toll-like receptors (TLRs) may contribute to the pathogenesis of chronic inflammatory destructive diseases through the recognition of endogenous ligands produced on either inflammation or degeneration of the extracellular matrix. The presence of endogenous TLR agonists has been reported in rheumatoid joints. in the present study, we investigated the significance of TLR2 and TLR4 activation by locally-produced endogenous ligands in the severity of joint inflammation and destruction. Local joint pathology independent of systemic immune activation was induced by overexpression of interleukin (IL)-1 and TNF in naive joints using adenoviral gene transfer. Here, we report that at certain doses, IL-1-induced local joint inflammation, cartilage proteoglycan depletion, and bone erosion are dependent on TLR4 activation, whereas TLR2 activation is not significantly involved. In comparison, tumor necrosis factor a-driven joint pathology seemed to be less dependent on TLR2 and TLR4. The severity of IL-1-induced bone erosion and irreversible cartilage destruction was markedly reduced in TLR4(-/-) mice, even though the degree of inflammation was similar, suggesting uncoupled processes. Furthermore, the expression of cathepsin K, a marker for osteoclast activity, induced by IL-1 beta was dependent on TLR4. Overexpression of IL-1 beta in the joint as well as ex vivo IL-1 stimulation of patellae provoked the release of endogenous TLR4 agonists capable of inducing TLR4-mediated cytokine production. These data emphasize the potential relevance of TLR4 activation in rheumatoid arthritis, particularly with respect to IL-1-mediated joint pathology. (Am J Pathol 2009, 175:2004-2013; DOI: 10.2353/ajpath.2009.090262)