Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain. Here, we reviewed the literature of the past 5 years with a focus on how TLRs may contribute to joint damage and pain in OA. We discuss biological effects of specific damage-associated molecular patterns (DAMPs) which act as TLR ligands in vitro, including direct effects on pain-sensing neurons. We then discuss the phenotype of transgenic mice that target TLR pathways, and provide evidence for a complex balance between pro- and anti-inflammatory signaling pathways activated by OA DAMPs. Finally, we summarize clinical evidence implicating TLRs in OA pathogenesis, including polymorphisms and surrogate markers of disease activity. Our review of the literature led us to propose a model where multi-directional crosstalk between connective tissue cells (chondrocytes, fibroblasts), innate immune cells, and sensory neurons in the affected joint may promote OA pathology and pain.

中文翻译：

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Toll样受体在骨关节炎的神经免疫界面上的新兴作用。

骨关节炎（OA）是滑膜关节的一种慢性进行性疼痛疾病，其特征是软骨退化，软骨下骨重塑，骨赘形成和滑膜炎。现在已经广泛认识到，先天免疫系统，特别是Toll样受体（TLR），促成OA关节组织的病理变化。此外，现在也越来越认识到，TLR信号传导在引发和维持疼痛中起着关键作用。在这里，我们回顾了过去5年的文献，重点介绍了TLRs如何导致OA的关节损伤和疼痛。我们讨论了特定的损伤相关分子模式（DAMP）的生物学效应，该分子在体外起着TLR配体的作用，包括对痛觉神经元的直接作用。然后，我们讨论靶向TLR途径的转基因小鼠的表型，并为由OA DAMP激活的促炎和抗炎信号通路之间的复杂平衡提供证据。最后，我们总结了涉及TLRs的OA发病机理的临床证据，包括多态性和疾病活动的替代标记。我们对文献的回顾使我们提出了一个模型，在该模型中，受影响关节中结缔组织细胞（软骨细胞，成纤维细胞），先天免疫细胞和感觉神经元之间的多方向串扰可能会促进OA病理和疼痛。