Porphyromonas gingivalis lipids mediate bone loss through TLR2

牙龈卟啉单胞菌脂质通过 TLR2 介导骨质流失

• 批准号: 9507134
• 负责人: FRANK C NICHOLS
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507134
• 关键词: Address; Adult; Affect; Agonist; Alveolar Bone Loss; Animals; Arterial Fatty Streak; Arteries; Atherosclerosis; Bacteria; Bacteroidetes; Biological; Bone Marrow; Bone Tissue; Cell physiology; Cells; Chronic; Complex; Dipeptides; Disease; Enzymes; Esterification; Exposure to; Gingival Diseases; Goals; High Pressure Liquid Chromatography; Human; Hydrolysis; Immune; In Vitro; Inflammation; Innate Immune System; Intestines; Knock-out; Lead; Lipids; Lipoproteins; Location; Mass Spectrum Analysis; Mediating; Medical; Microbe; Oral; Organism; Osteoblasts; Parents; Pathogenesis; Periodontal Diseases; Periodontitis; Phospholipase A2; Phospholipids; Porphyromonas gingivalis; Preparation; Process; Prostaglandins; Protein Isoforms; Reporting; Research; Role; Sampling; Serine; Site; Structure; Structure of gingival sulcus; TLR2 gene; TNF gene; Time; Tissues; Tooth Diseases; Tooth structure; Work; alveolar bone; bone cell; bone loss; bone metabolism; cytokine; defense response; experimental study; extracellular; in vivo; inhibitor/antagonist; knockout animal; macrophage; novel; oral infection; osteoblast differentiation; osteoclastogenesis; pathogen; receptor; response; uptake; wisdom tooth

Porphyromonas gingivalis is a periodontal pathogen implicated in the initiation and progression of chronic periodontitis in adults. We recently demonstrated that this organism produces two novel classes of serine lipids that inhibit bone cell function and activate macrophages to release important cytokines. At least one of these serine lipids also mediates its effects on bone cells and macrophages through engagement of the innate immune system, specifically through Toll Receptor 2 (TLR2). Understanding how these lipids promote TLR2- dependent cellular effects is relevant specifically to the reported effects of P. gingivalis on periodontal bone loss in experimental animals. Since all Bacteroidetes appear to be capable of producing these serine lipids, including intestinal Bacteroidetes, their role in other medical diseases, such as atherosclerosis, may also be important. P. gingivalis serine lipids are unusual in that a mammalian enzyme called phospholipase A2 (PLA2) can hydrolyze the dominant serine lipid to a de-esterified form that is even more potent than the parent lipid in inhibiting bone cells. Of note, chronic inflammation is associated with increased expression of PLA2 which results in elevated prostaglandin levels within chronically inflamed tissues. However, only one chiral form of the parent serine lipid is hydrolyzed by PLA2. This application proposes to first quantify the levels of each chiral form of the parent serine lipids in common oral Bacteroidetes. Next, we will investigate hydrolysis of the each chiral form of the parent serine lipid by macrophages and osteoblasts. This will determine the importance of intracellular versus extracellular hydrolysis of the different chiral forms and the relevance of the location of lipid hydrolysis to biological activity. Finally, we will determine which cellular PLA2 enzyme classes are responsible for the hydrolysis of the parent lipid. We will examine the role of TLR2 in these processes by comparing bacterial lipid effects in bone cells isolated from either wild type or TLR2 knockout animals. The experiments summarized in this proposal are critical to explaining how P. gingivalis promotes TLR2-dependent bone loss in periodontal diseases. In addition, the discovery that the PLA2 enzyme will hydrolyze the parent serine lipid to a de-esterified serine lipid of greater potency is potentially important in other medical conditions where bacterial lipids accumulate, including atherosclerotic plaques.

牙龈卟啉单胞菌（Porphyromonas gingivalis）是一种与慢性牙周炎的发生和发展有关的牙周病原体。 成人牙周炎。我们最近证明，这种生物体产生两种新的丝氨酸 抑制骨细胞功能并激活巨噬细胞释放重要细胞因子的脂质。中的至少一 这些丝氨酸脂质还通过与先天性巨噬细胞的结合介导其对骨细胞和巨噬细胞的作用。 免疫系统，特别是通过Toll受体2（TLR 2）。了解这些脂质如何促进TLR 2- 依赖性细胞效应与牙龈卟啉单胞菌对牙周骨的影响有关 实验动物的损失。由于所有拟杆菌似乎都能产生这些丝氨酸脂质， 包括肠道拟杆菌，它们在其他医学疾病，如动脉粥样硬化中的作用也可能是 重要.牙龈卟啉单胞菌丝氨酸脂质是不寻常的，因为哺乳动物的酶称为磷脂酶A2（PLA 2） 可以将主要的丝氨酸脂质水解成去酯化形式， 抑制骨细胞值得注意的是，慢性炎症与PLA 2表达增加有关， 导致慢性炎症组织内前列腺素水平升高。然而，只有一种手性形式 母体丝氨酸脂质被PLA 2水解。本申请建议首先量化每种物质的水平 常见口腔拟杆菌中母体丝氨酸脂质的手性形式。接下来，我们将研究 母体丝氨酸脂质的每一种手性形式被巨噬细胞和成骨细胞吸收。这将决定 不同手性形式的细胞内与细胞外水解的关系以及 脂质水解的生物活性。最后，我们将确定哪些细胞PLA 2酶类是 负责母体脂质的水解。我们将研究TLR 2在这些过程中的作用， 比较从野生型或TLR 2敲除动物分离的骨细胞中的细菌脂质作用。的 本提案中总结的实验对于解释牙龈卟啉单胞菌如何促进TLR 2依赖性 牙周病引起的骨质流失此外，发现PLA 2酶将水解母体 丝氨酸脂质转化为更大效力的去酯化丝氨酸脂质在其它医学病症中是潜在重要的 其中细菌脂质积累，包括动脉粥样硬化斑块。