Invasive Bacteria Accelerate Atherosclerosis through TLRs

入侵细菌通过 TLR 加速动脉粥样硬化

• 批准号: 7049670
• 负责人: Caroline A Genco
• 金额: $ 40.25万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049670
• 关键词: Bacteroides gingivalis; aorta; apolipoprotein E; atherosclerosis; atherosclerotic plaque; bacteria infection mechanism; binding proteins; biological signal transduction; dietary lipid; genetically modified animals; host organism interaction; immunocytochemistry; inflammation; laboratory mouse; microorganism immunology; oral bacteria; receptor expression; toll like receptor

DESCRIPTION (provided by applicant): Accumulating evidence has implicated specific infectious agents, including Chlamydia pneumoniae and Porphyromonas gingivalis in the progression of atherosclerosis. However, the mechanisms by which infections contribute to the progression of atherosclerosis and the links among lipids, microbial antigens, and innate immune and inflammatory responses are not well understood. Toll-like receptors (TLR) are pattern recognition receptors that have key roles in detecting microbes and initiating inflammatory responses. Recently, expression of TLRs has been demonstrated, to be markedly augmented in human atherosclerotic lesions. Our studies indicate that TLR2 and TLR4 expression is enhanced in mouse atherosclerotic lesions following oral challenge with P. gingivalis in an apoE model of atherosclerosis. These are the first studies with any bacterial pathogen that have demonstrated a link between innate immune markers and infection-accelerated atherosclerosis in an animal model. In addition, we have demonstrated that TLR2, TLR4, and MyD88 (cytoplasmic adapter molecule) are required for host cell signaling in response to P. gingivalis and that TLR2 and MvD88 are required for local inflammation associated with P. gingivalis infection in a murine model. TLR2 and TLR4 expression is also enhanced in endothelial cells and macrophages in response to P. gingivalis infection and following infection, these cells become primed to respond to TLR4-ligands. Recent studies using TLR4 and MyD88 / ApoE mice have shown a substantial reduction in atherosclerosis lesion development compared to wildtype mice fed a high fat diet supporting the direct involvement of the TLR4 and MyD88-dependent signaling pathway in the development of lipid induced atherosclerosis in mice. Furthermore, our initial analysis of newly generated TLR2 / ApoE mice demonstrate that these mice develop less atherosclerotic plaque as compared to ApoE mice. Together these results raise the possibility that enhanced TLR expression and signaling may play a role in infection accelerated inflammation and atherosclerosis. The aims of this study are: 1. To define the role of bacterial induced systemic and aortic inflammation in the acceleration of atherosclerotic plaque accumulation in ApoE -/- mice orally challenged with P.-gingivalis at the acute phase. 2. To assess the role of TLR-MyD88-dependent signaling in atheromatous plaque development following P. gingivalis oral challenge. 3. To assess the role of the TLR-2 and TLR-4-dependent signaling pathway in atheromatous plaque development following P. gingivalis oral challenge. Improved understanding of the molecular mechanisms driving TLR over expression and signaling and the role of the resulting chronic inflammation during atherosclerosis may provide new targets for therapy.

描述（由申请人提供）：累积证据牵涉到特定的感染因子，包括肺炎衣原体和牙龈牙龈变虫，在动脉粥样硬化的进展中。然而，感染的机制有助于动脉粥样硬化的进展以及脂质，微生物抗原以及先天免疫和炎症反应之间的联系。 Toll样受体（TLR）是模式识别受体，在检测微生物和引发炎症反应中具有关键作用。最近，已经证明了TLR的表达，可以在人动脉粥样硬化病变中显着增强。我们的研究表明，在动脉粥样硬化模型中，口服牙龈疟原虫在口腔挑战后，小鼠动脉粥样硬化病变中TLR2和TLR4的表达增强。这些是对任何细菌病原体的首次研究，这些病原体已经证明了在动物模型中先天免疫标记与感染加速性动脉粥样硬化之间的联系。此外，我们已经证明了TLR2，TLR4和MYD88（细胞质衔接子分子）是响应于牙龈螺地的宿主细胞信号传导所必需的，并且TLR2和MVD88是与鼠模型中与Gingivalis感染相关的局部炎症所必需的。 TLR2和TLR4的表达在响应牙龈疟原虫感染的响应和感染后，内皮细胞和巨噬细胞的表达也得到了增强，这些细胞开始启动以响应TLR4-cligands。使用TLR4和MYD88 / APOE小鼠的最新研究表明，与喂养高脂肪饮食的野生型小鼠相比，动脉粥样硬化病变的发育显着降低，这些小鼠支持高脂饮食，支持TLR4的直接参与TLR4和MyD88依赖性信号传导途径在小鼠中脂动脉粥样硬化诱导的动脉粥样硬化发育中。此外，我们对新生成的TLR2 / APOE小鼠的初始分析表明，与APOE小鼠相比，这些小鼠的动脉粥样硬化斑块较少。这些结果共同提高了TLR表达和信号传导可能在感染加速炎症和动脉粥样硬化中发挥作用的可能性。这项研究的目的是：1。定义细菌诱导的全身性和主动脉炎症在APOE-/ - 小鼠中在急性期口服挑战的APOE-/ - 小鼠中动脉粥样硬化斑块积累加速中的作用。 2。评估TLR-MYD88依赖性信号传导在口服牙龈疟原虫后的动脉瘤发育中的作用。 3。评估TLR-2和TLR-4依赖性信号传导途径在口服牙龈疟原虫后的动脉瘤发育中的作用。对驱动TLR驱动TLR的分子机制的理解提高了表达和信号传导，以及在动脉粥样硬化期间所产生的慢性炎症的作用可能为治疗提供了新的靶标。