Innate Immune Mechanisms Involved in P. Gingivalis-Induced Chronic Inflammation

致病菌肺炎衣原体和牙龈卟啉单胞菌可诱导慢性牙周炎 发炎。在人类和小鼠模型中的流行病学研究支持C. 肺炎支原体和牙龈假单胞菌在慢性炎性斑块中聚集。然而，这些是如何 病原体引发和维持慢性炎症的定义还不清楚。促炎细胞因子 包括IL-1B、肿瘤坏死因子和IL-6在慢性炎症中起关键作用。众所周知，人类 炎性血管斑块与IL-1受体拮抗剂基因多态性相关 基因和IL-1在细菌诱导的炎性血管斑块聚集中的作用 老鼠。IL-1B基因多态性与牙龈假单胞菌介导的人类炎症相关 牙周病。在这个项目中，我们将检验以下假设：1)IL-1B的诱导 在内皮细胞中通过一种明确的机制发生，导致刺激功能性 血小板和巨噬细胞的反应；2)IL-1在慢性口腔疾病中起关键作用 与牙龈假单胞菌相关的炎症性骨丢失和炎性斑块形成 通过细胞特定机制的慢性感染。为了检验这些假设，我们提出了以下建议 目的：目的：1.明确牙龈假单胞菌诱导1L1-B的机制 小鼠内皮细胞和IL-1B如何调节血小板和巨噬细胞功能。目标2.目标 确定IL-1和细胞特异性在牙龈假单胞菌诱导的口腔炎症表达中的作用 小鼠模型中的骨质丢失。目的3.明确IL-1和细胞特异性在表达中的作用 在牙龈假单胞菌诱导的小鼠模型中，慢性炎症和菌斑堆积。项目 4和项目1-3将确定特定的先天免疫信号分子在P. 牙周炎和肺炎衣原体诱导慢性牙周炎相关细胞的炎症反应 炎症过程，将表征这些先天免疫途径在 体内的炎症过程，并确定这些反应中的细胞特异性。

The pathogenic bacteria Chlamydophila pneumoniae and Porphyromanas gingivalis induce chronic inflammation. Epidemiological studies in humans and mouse models support a role for C. pneumoniae and P. gingivalis in chronic inflammatory plaque accumulation. IHowever, how these pathogens induce and maintain chronic inflammation is not well defined. Proinflammatory cytokines including IL-1B , TNF, and IL-6 play a critical role in chronic inflammation. It is known that human inflammatory vascular plaque is associated with polymorphisms in the IL-1 receptor antagonist gene and that IL-1 plays a role in bacterial induced inflammatory vascular plaque accumulation in mice. IL-1B polymorphisms are also associated with P. gingivalis mediated human inflammatory periodontal disease. In this project we will test the following hypotheses: 1) The induction of IL-1B occurs via a defined mechanism in endothelial cells which leads to stimulation of functional responses in platelets and macrophages; and 2) IL-1 plays a critical role in chronic oral inflammatory bone loss and inflammatory plaque formation that is associated with P. gingivalis chronic infection via cell specific mechanisms. To test these hypotheses we propose the following Aims: Aim 1. To define the mechanism by which 1L1-B is induced in response to P. gingivalis in mouse endothelial cells and how IL-1 B modulates platelet and macrophage function. Aim 2. To define the role of lL-1 and cell specificity in expression in P. gingivalis induced oral inflammatory bone loss in a mouse model. Aim 3. To define the role of IL-1 and cell specificitv in expression in P. gingivalis induced chronic inflammation and plaque accumulation in a mouse model. Project 4 together with Projects 1- 3 will define the role of specific innate immune signaling molecules in P. gingivalis and C. pneumoniae induced inflammatory responses in cells relevant to chronic inflammatory processes, will characterize the roles of these innate immune pathways in inflammatory processes in vivo and define cell specificitv in these responses.