Interferon Regulatory Factors and Periodontal Disease

描述（由申请人提供）：由居住在口腔中的一群细菌引起的炎症，如牙龈卟啉单胞菌（Pg），是牙周病（PD）的一个关键方面。这种慢性炎症被认为会导致硬组织和软组织的破坏，在严重的疾病中会导致牙齿脱落。出乎意料的是，在人PD组织中检测到1型干扰素、干扰素(IFN)-1以及干扰素诱导的激活正常T细胞表达和分泌调节蛋白（RANTES）水平升高。这是出乎意料的，因为1型干扰素是对病毒感染的先天免疫反应的一部分。这些干扰素在PD中的作用基本上是未知的。干扰素调节因子（IRF）是用于生产1型干扰素的主要转录因子。这些转录因子还调节其他已知与炎症有关的基因组的表达。IRF3和IRF7信号与宿主对牙周病原体的反应有关；然而，目前尚不清楚干扰素信号如何参与牙周病原体炎症病灶的建立。我们的初步数据发现Pg培养的野生型巨噬细胞中ifnb1基因的表达增加。此外，WT和IRF3- ko小鼠的巨噬细胞培养活Pg表明IRF3在促炎细胞因子和趋化因子的产生中起部分作用。在这里，我们提出了一组详细的相关研究，以开始表征宿主对牙周病原体反应的一个鲜为人知的领域，即IRF3信号的作用和Pg引起的炎症的建立。这些研究将为未来扩大研究铺平道路，以确定慢性炎症和口腔骨质流失背景下IRF3信号的确切机制，与PD相关的标志物。这项工作的最终目标是开始了解干预irf3信号的策略是否可以被引导以增强当前的PD治疗方案。

DESCRIPTION (provided by applicant): Inflammation elicited by a subset of bacteria that inhabit the oral cavity such as Porphyromonas gingivalis (Pg) is a key facet of periodontal disease (PD). This chronic inflammation is thought to drive the destruction of both hard and soft tissues that in severe disease leads to tooth loss. Unexpectedly, elevated levels of the type 1 interferon, interferon (IFN)-1, as well as the interferon-induced protein Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) has been detected in human PD tissues. This is unexpected as type 1 interferons are part of the innate immune response to viral infection. The role of these interferons in PD is essentially unknown. Interferon regulatory factors (IRF) are the principal transcriptional factors used for production of type 1 interferons. These transcription factors also regulate expression of other groups of genes known to be involved in inflammation. IRF3 and IRF7 signaling have been implicated in host response to periodontal pathogens; however, it is unclear precisely how interferon signaling participates in the establishment of a nidus of inflammation to periodontal pathogens. Our preliminary data identify increased expression of the ifnb1 gene from wild type macrophages cultured with Pg. Furthermore, culture of live Pg with macrophages from WT and IRF3-KO mice demonstrate a partial role for IRF3 in pro-inflammatory cytokine and chemokine production. Here we propose a detailed set of related studies to begin to characterize a poorly understood area of host response to periodontal pathogens, namely the role of IRF3 signaling and with establishment of inflammation elicited by Pg. These studies will pave the way for future expanded investigations to define the precise mechanisms underlying IRF3 signaling in the context of chronic inflammation and oral bone loss, markers associated with PD. The ultimate goal of this work is to begin to understand whether strategies to intercede in IRF3-signaling can be channeled to augment current PD treatment regimens. PUBLIC HEALTH RELEVANCE: Type 1 Interferons, such as interferon-1, are key mediators of the immune response to pathogenic virus infection. Emerging data indicate that type 1 interferons are produced as part of the host response to bacterial infections; however, this area is exceedingly understudied in the context of periodontal disease. Based on our preliminary data we propose a focused set of studies to 1- define production of and 2- mechanism underlying host type 1 interferon production to the periodontal pathogen Porphyromonas gingivalis.