Interactions of Oral Pathogens With Toll-Like Receptors: Possible Role in Atherosclerosis

George Hajishengallis Dr., Ashu Sharma, Michael W. Russell, Robert J. Genco
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引用次数: 101

Abstract

Toll-like receptors (TLR) function as important signal transducers that mediate innate immune and inflammatory responses to pathogens through pattern recognition of virulence molecules. Although TLRs mediate protection against infection, it is also likely that they may have a pathophysiologic role in certain inflammatory diseases, such as atherosclerosis. In atherosclerotic lesions, endothelial cells and macrophages have been shown to upregulate TLR expression and may respond to TLR agonists of microbial origin, resulting in detrimental inflammatory reactions. Some of these potential TLR-activating virulence factors may be of oral origin. The detection in atherosclerotic plaques of DNA specific for Porphyromonas gingivalis and other periodontal pathogens suggests that these pathogens disseminate into the systemic circulation and localize in atheromas. The potential of periodontal and some other oral pathogens to activate TLRs in vivo is suggested by findings from cell culture experiments on interactions of selected virulence protein adhesins with TLRs and their coreceptors. Specifically, we have shown that proinflammatory cytokine induction by P. gingivalis fimbriae was inhibited by monoclonal antibodies to TLR2, TLR4, CD14, and beta2 integrins, but not by immunoglobulin isotype controls. Cytokine induction by Bacteroides forsythus protein A depended heavily on CD14 and TLR2. We also found that the ability of Streptococcus mutans protein AgI/II to stimulate cytokine release was partially dependent on CD14 and TLR4. Moreover, P. gingivalis fimbriae induced TLR-dependent activation of nuclear factor-kappaB and upregulation of costimulatory molecules in monocytic cells. These proinflammatory activities have been implicated in the pathogenesis of periodontitis, and similar inflammatory mechanisms could potentially operate in atherosclerosis. Studies by other groups have shown that P. gingivalis is capable of stimulating low-density lipoprotein oxidation, foam cell formation, and rupture of atherosclerotic plaque through induction of matrix metalloproteinases. Interestingly, at least some of these activities can be induced by TLR agonists (lipopolysaccharide and heat-shock protein-60) from Chlamydia pneumoniae, a major risk factor in atherosclerosis. Future research in animal models and in vitro cellular systems with defined mutations in TLRs may implicate TLR participation in oral pathogen-mediated atherosclerotic processes, thereby providing a mechanistic basis for the epidemiological findings linking oral pathogens to atherosclerotic disease.
口腔病原体与toll样受体的相互作用:在动脉粥样硬化中的可能作用
toll样受体(TLR)作为重要的信号转导器,通过对毒力分子的模式识别介导对病原体的先天免疫和炎症反应。虽然tlr介导对感染的保护,但它们也可能在某些炎症性疾病(如动脉粥样硬化)中具有病理生理作用。在动脉粥样硬化病变中,内皮细胞和巨噬细胞上调TLR表达,并可能对微生物来源的TLR激动剂产生反应,导致有害的炎症反应。一些潜在的激活tlr的毒力因子可能是口服的。在动脉粥样硬化斑块中检测到牙龈卟啉单胞菌和其他牙周病原体的特异性DNA,表明这些病原体传播到体循环并局限于动脉粥样硬化。在细胞培养实验中,选定的毒力蛋白粘附素与tlr及其辅受体相互作用的结果表明,牙周和其他口腔病原体有可能在体内激活tlr。具体来说,我们已经表明,牙龈假单胞菌菌毛的促炎细胞因子诱导被TLR2、TLR4、CD14和β2整合素的单克隆抗体抑制,但不受免疫球蛋白同型对照的抑制。连翘拟杆菌蛋白A对细胞因子的诱导依赖于CD14和TLR2。我们还发现变形链球菌蛋白AgI/II刺激细胞因子释放的能力部分依赖于CD14和TLR4。此外,牙龈假单胞菌菌毛诱导单核细胞中核因子-κB的tlr依赖性激活和共刺激分子的上调。这些促炎活动与牙周炎的发病机制有关,类似的炎症机制可能在动脉粥样硬化中起作用。其他研究小组的研究表明,牙龈卟啉卟啉能够通过诱导基质金属蛋白酶刺激低密度脂蛋白氧化、泡沫细胞形成和动脉粥样硬化斑块破裂。有趣的是,至少其中一些活性可以由来自肺炎衣原体的TLR激动剂(脂多糖和热休克蛋白-60)诱导,这是动脉粥样硬化的主要危险因素。未来在动物模型和体外细胞系统中确定TLR突变的研究可能暗示TLR参与口腔病原体介导的动脉粥样硬化过程,从而为将口腔病原体与动脉粥样硬化疾病联系起来的流行病学发现提供机制基础。Ann periodontoto2002;7:72-78。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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