Epithelial Cell Function in the Progression of Periodontal Disease

描述(申请人提供)：牙周病是炎症性疾病的一类，如果不治疗，可能会导致软硬组织破坏。虽然微生物是牙周病的病原体，但易感宿主的有害炎症反应可能会加剧疾病。口腔上皮细胞是抵御口腔内微生物感染的第一道防线。这些重要的细胞在粘膜表面起着多种作用。 包括它们可以作为非造血性先天免疫细胞发挥作用(与传统的造血性白细胞不同)，直接促进先天免疫，并在粘膜动态平衡中发挥重要作用。天然免疫的过度激活或动态平衡的破坏可能导致局部炎症的启动和/或加重，如牙周病。因此，了解上皮细胞介导的免疫反应调节以预防和/或治疗口腔黏膜炎症是非常必要的。TLR信号转导结果的动态变化可归因于多种因素，包括TLR配体的类型(S)、TLR配体的浓度(S)、TLR配体刺激的持续时间(S)以及TLR配体参与的细胞类型(S)。事实上，我们的初步数据表明，人和小鼠口腔上皮细胞对TLR2刺激以耐受性方式反应，而TLR4刺激诱导促炎表型。在这里，我们提供了初步的数据，MYD88(一种关键的TLR信号分子)在口腔上皮细胞中被定向、可诱导地敲除，在牙周病的多微生物模型中加剧了软组织渗透和骨丢失。我们认为口腔上皮细胞中MYD88依赖的信号在控制炎症中发挥作用，从而限制局部炎症和预防牙周病。我们的假设是，口腔上皮细胞MYD88依赖的TLR信号导致耐受性免疫调节，从而抵消其他炎症反应。在这里，我们将描述口腔上皮细胞在牙周病发生/发展过程中的免疫调节机制。通过建立疾病进展的标志，我们将能够描绘出检查点，在那里可以应用新的干预措施来阻止或逆转牙周病炎症。此外，还将描述TLR受体的使用和有助于调节与炎症上皮细胞表型的信号事件，从而能够确定旨在减轻口腔上皮细胞相关性炎症的新型干预措施的靶点。最后，将测定一种抗炎剂在口腔上皮细胞依赖的急性牙周病模型中的体内疗效，并阐明其调节机制(S)。

DESCRIPTION (provided by applicant): Periodontal diseases are a class of inflammatory diseases which if left untreated can result in soft and hard tissue destruction. While microbes are etiological agents of periodontal disease, a harmful inflammatory response in a susceptible host can exacerbate disease. Oral epithelial cells are the first line of defense against microbial infection within the oral cavity. These important cells serve multiple roles at the mucosal surface including whereby they can function as non-hematopoietic innate immune cells (in contrast to traditional hematopoietic leukocytes) that contribute directly to innate immunity and play an important role in mucosal homeostasis. Over-activation of innate immunity or disruption of this homeostasis can result in initiation and/or exacerbation of localized inflammation as seen in periodontal diseases. Thus, it is imperative that we understand epithelial cell mediated regulation of immune responses to prevent and/or treat inflammation of oral mucosa. Dynamics of TLR signaling outcomes are attributable to several factors including the type of TLR ligand(s), concentration of TLR ligand(s), duration of stimulation by TLR ligand(s), and the cell type which is being engaged by TLR ligand(s). Indeed, our preliminary data demonstrates that both human and murine oral epithelial cells respond to TLR2 stimulation in a tolerogenic manner while TLR4 stimulation induces a pro- inflammatory phenotype. Here we present preliminary data whereby targeted, inducible knockout of MYD88 (a key TLR-signaling molecule) in oral epithelial cells exacerbated soft tissue infiltration and bone loss in a multi- microbial model of periodontal disease. We propose that MYD88-dependent signaling in oral epithelial cells plays a role in controlling inflammation thus limiting localized inflammation and averting periodontal disease. It is our hypothesis that oral epithelial cell MYD88-dependent TLR signaling causes tolerogenic immune tuning which counteracts otherwise inflammatory responses. Here we will delineate mechanisms of immune tuning by oral epithelial cells during periodontal disease initiation/progression. By establishing hallmarks of disease progression we will be able to delineate checkpoints at which novel interventions can be applied to halt or reverse periodontal disease inflammation. In addition, will delineate TLR-receptor usage and signaling events which contribute to regulatory versus inflammatory epithelial cell phenotypes, allowing for the identification of targets for novel interventions aimed at attenuating oral epithelial cell associaed inflammation. Finally, will determine in vivo efficacy of an anti- inflammatory agent in an oral epithelial cell dependent model of exacerbated periodontal disease and delineate the mechanism(s) of its regulation.