The Role of Histone Deacetylase 6 in Oral Bacteria-Mediated Periodontal Inflammation

项目摘要/摘要： 牙周炎是一种慢性炎症性疾病，由牙周组织内的细菌感染引起， 几乎50%的美国成年人。这一区域未解决的炎症导致眼球破裂 牙周膜和牙槽骨，可导致后续牙齿脱落。虽然细菌的存在 引发牙周炎，但它最终并不是推动疾病进展的唯一因素。炎症性的 反应对于根除细菌入侵者至关重要，但这些机制和机制的失调 促炎细胞因子如肿瘤坏死因子-α、白介素6、白介素12p40的过度产生和巨噬细胞炎症 蛋白2(MIP-2)与牙周组织和其他组织损伤的进展有关 慢性炎症性疾病。组蛋白脱乙酰酶6(HDAC6)是第二类HDACs的成员，位于 一种细胞质，可以使特定的非组蛋白去乙酰化，并促进它们向细胞核的移位。 据报道，这种去乙酰化可以改变炎症介质的产生，以响应刺激 微生物相关分子模式(MAMP)。我们的初步结果表明，刺激 牙龈卟啉单胞菌是一种与慢性牙周炎相关的主要病原菌 牙周炎，导致第二类HDAC的磷酸化和随后的FoxO1的脱乙酰化，这将 增强其与FoxO结合元件的结合，从而促进相关的促炎介质 制作。同样，选择性抑制HDAC6会导致促炎细胞因子的减少 通过增加FoxO1的胞质转位而产生，随后减少了它与 牙龈假单胞菌感染后C/eBP-β启动子的表达因此，使用牙龈假单胞菌作为模式生物，我们 假设口腔细菌病原体激活HDAC6并增强炎症反应 通过促进FoxO1的脱乙酰化和核转位，从而增强 下游促炎介质的表达。我们将使用两个目标来检验这一假设。 为目标1提出的实验将通过观察HDAC6在炎症反应中的作用来研究 炎性细胞因子的产生和中性粒细胞的迁移，也将描绘下游 HDAC6在不同免疫细胞中的信号转导响应牙龈假单胞菌攻击。在目标2中，我们将研究 HDAC6信号在口腔细菌感染和牙周组织炎症反应中的体内相关性 牙槽骨丢失。这些目的将建立HDAC6介导的差别性炎症的调节功能 调节免疫反应的中介物分泌。这项拟议工作的长期目标将是 确定新的牙周炎介入治疗靶点和调节机制，可能 广泛适用于其他炎症性疾病。

Project Summary/Abstract: Periodontitis is a chronic inflammatory disease induced by bacterial infection within the periodontium and affects almost 50% of adults in the United States. Unresolved inflammation in this area results in the breakdown of the periodontal ligament and alveolar bone which can lead to subsequent tooth loss. While the presence of bacteria initiates periodontitis, it is ultimately not the sole factor that drives disease progression. The inflammatory response is critical for the eradication of bacterial invaders, however the dysregulation of these mechanisms and overproduction of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12 p40, and Macrophage Inflammatory Protein 2 (MIP-2) have been implicated in the progression of tissue damage in the periodontium and in other chronic inflammatory diseases. Histone deacetylase 6 (HDAC6) is a member of the class II HDACs located in the cytoplasm that can deacetylate specific non-histone proteins and facilitate their translocation to the nucleus. This deacetylation has been reported to alter production of inflammatory mediators in response to the stimulation of microbe-associated molecular patterns (MAMPs). Our preliminary results have shown that stimulation of innate immune cells with Porphyromonas gingivalis, a major pathogenic bacterium associated with chronic periodontitis, resulted in phosphorylation of class II HDACs and subsequent deacetylation of FoxO1, which will enhance its binding to the FoxO-binding element and thus promote associated pro-inflammatory mediator production. Likewise, selective inhibition of HDAC6 resulted in a decrease in pro-inflammatory cytokine production through increasing cytosolic translocation of FoxO1 and subsequently decreased its binding to the promoter of C/EBP-β after P. gingivalis infection. Therefore, using P. gingivalis as a model organism, we hypothesize that oral bacterial pathogens activate HDAC6 and enhance the inflammatory response through facilitating the deacetylation and nuclear translocation of FoxO1, subsequently enhancing the expression of downstream pro-inflammatory mediators. We will test this hypothesis using two aims. Experiments proposed for Aim 1 will investigate the role of HDAC6 in the inflammatory response by observing the production of inflammatory cytokines and the migration of neutrophils and will also delineate the downstream signaling of HDAC6 in different immune cells in response to P. gingivalis challenge. In Aim 2, we will examine the in vivo relevancy of HDAC6 signaling in gingival tissue inflammatory responses to oral bacterial infection and alveolar bone loss. These aims will establish the regulatory function of HDAC6-mediated differential inflammatory mediator secretion in the control of immune responses. The long-term goal of this proposed work will be to identify novel interventional therapeutic targets and regulatory mechanisms of periodontal inflammation that may be broadly applicable to other inflammatory diseases.