Periodontal disease is driven by dysbiosis of the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola , is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed a significant upregulation of genes associated with extracellular matrix organization and degradation, including tissue-specific inducible MMPs that may play novel roles in modulating host immune responses yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula , failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of either TLR2 or MyD88 abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs, whereas a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola -mediated activation of TLR2/MyD88 led to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola- dependent MMP expression. Taken together, these data support that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.

中文翻译：

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密闭螺旋体齿质素触发TLR2 / MyD88激活上调人口腔细胞中通过Sp1参与MMP的组织破坏性程序

牙周疾病是由口腔微生物组的代谢异常所驱动，导致过度表达引起牙周炎性细胞因子，趋化因子和组织重塑基质金属蛋白酶（MMP）释放的物种。这些慢性组织破坏性炎症反应导致支持牙齿的牙槽骨逐渐丢失。持续发现牙周螺旋体的口腔螺旋体密螺旋体水平明显升高。宿主表达的Toll-like Receptor 2（TLR2）可以感应各种细菌配体，包括酰化的脂多糖和脂蛋白。T. denticola dentilisin，一种由三种脂蛋白组成的表面表达蛋白酶复合物，已被认为是牙周疾病的致病因子，主要是由于其蛋白水解活性。尽管已充分研究了酰化细菌成分在诱导炎症中的作用，但很少关注牙本质素的酰化性质的潜在作用。这项研究的目的是检验假单胞菌牙本质蛋白酶激活TLR2依赖性机制，从而导致牙周组织中的组织破坏性基因上调的假说。牙周线虫细菌攻击的牙周膜细胞的RNA测序显示与细胞外基质组织和降解相关的基因显着上调，包括可能在调节宿主免疫反应中发挥新作用的组织特异性诱导型MMP，尚待本文进行表征口腔疾病。革兰氏阴性口服小菜蛾Veillonella parvula无法上调这些相同的MMP。DTL诱导的MMPs上调是通过TLR2和MyD88激活介导的，因为TLR2或MyD88的敲低消除了这些作用。纯化牙本质素的挑战会上调相同的MMP，而缺乏牙本质素的T. denticola突变体则没有作用。最后，T。denticola介导的TLR2 / MyD88激活导致转录因子Sp1的核易位，该转录因子被证明是所有T. denticola依赖性MMP表达的关键调节剂。综上所述，这些数据支持T. denticola dentilisinin以TLR2 / MyD88 / Sp1依赖性方式刺激组织破坏性细胞过程。denticola突变体无效。最后，T。denticola介导的TLR2 / MyD88激活导致转录因子Sp1的核易位，该转录因子被证明是所有T. denticola依赖性MMP表达的关键调节剂。综上所述，这些数据支持T. denticola dentilisinin以TLR2 / MyD88 / Sp1依赖性方式刺激组织破坏性细胞过程。denticola突变体无效。最后，T。denticola介导的TLR2 / MyD88激活导致转录因子Sp1的核易位，该转录因子被证明是所有T. denticola依赖性MMP表达的关键调节剂。综上所述，这些数据支持T. denticola dentilisinin以TLR2 / MyD88 / Sp1依赖性方式刺激组织破坏性细胞过程。