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

项目概要/摘要： 牙周炎是一种由牙周组织内细菌感染引起的慢性炎症性疾病， 几乎50%的美国成年人。未解决的炎症在这方面的结果在崩溃的 牙周韧带和牙槽骨，这可能导致随后的牙齿脱落。虽然细菌的存在 虽然牙周炎是牙周炎的始作俑者，但它最终不是驱动疾病进展的唯一因素。炎症 反应对于根除细菌入侵者至关重要，然而这些机制的失调和 促炎细胞因子如TNF-α、IL-6、IL-12 p40和巨噬细胞炎性因子的过度产生 蛋白2（MIP-2）与牙周组织损伤的进展和其他组织损伤有关。 慢性炎症性疾病。组蛋白去乙酰化酶6（HDAC 6）是II类HDACs的成员，位于 能使特定的非组蛋白质脱乙酰基并促进其转移到细胞核的细胞质。 据报道，这种脱乙酰化会改变炎症介质响应刺激的产生 微生物相关分子模式（MAMPs）我们的初步研究结果表明， 先天免疫细胞与牙龈卟啉单胞菌，一种与慢性牙龈炎相关的主要致病菌 牙周炎，导致II类HDAC的磷酸化和随后的FoxO 1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 生产同样，选择性抑制HDAC 6导致促炎细胞因子减少 通过增加FoxO 1的胞质易位产生，随后降低其与 牙龈卟啉单胞菌感染后C/EBP-β启动子的表达。因此，使用牙龈卟啉单胞菌作为模式生物，我们 假设口腔细菌病原体激活HDAC 6并增强炎症反应 通过促进FoxO 1的去乙酰化和核转位， 下游促炎介质的表达。我们将用两个目标来检验这个假设。 针对目的1提出的实验将通过观察HDAC 6在炎症反应中的作用来研究HDAC 6在炎症反应中的作用。 炎性细胞因子的产生和中性粒细胞的迁移，也将描绘下游 HDAC 6在不同免疫细胞中响应牙龈卟啉单胞菌攻击的信号传导。在目标2中，我们将研究 HDAC 6信号在牙龈组织炎症反应对口腔细菌感染的体内相关性， 牙槽骨丢失。这些目标将建立HDAC 6介导的差异性炎症反应的调节功能。 介体分泌控制免疫反应。这项拟议工作的长期目标是 确定新的牙周炎介入治疗靶点和调节机制， 可广泛应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.