Porphyromonas gingivalis glycine lipids mediate bone loss through TLR2

牙龈卟啉单胞菌甘氨酸脂质通过 TLR2 介导骨质流失

• 批准号: 10327687
• 负责人: FRANK C NICHOLS
• 金额: $ 38.56万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327687
• 关键词: Address; Adult; Aftercare; Age; Agonist; Alveolar Bone Loss; Animals; Bacteroidetes; Biological; Bone Marrow; Bone Resorption; Bone Tissue; Calculi; Cell Line; Cell physiology; Cells; Chronic; Complex; Disease; Epithelial; Epithelial Cells; Etiology; Exposure to; Fibroblasts; Genetic Engineering; Gingiva; Gingival Diseases; Glycine; Goals; Human; Hydrolysis; Immune; Immune response; Inflammation; Inflammation Mediators; Innate Immune System; Laboratories; Lead; Lipids; Macrophage Colony-Stimulating Factor; Mediating; Microbe; Mus; Organism; Osteoclasts; Parasites; Periodontal Diseases; Periodontitis; Phospholipase A2; Porphyromonas gingivalis; Process; Prostaglandins; Reporting; Research Personnel; Sampling; Serine; Site; Source; TLR1 gene; TLR2 gene; TLR6 gene; Testing; Tissues; Toll-like receptors; Tooth Diseases; Tooth structure; Virulence Factors; Work; alveolar bone; bone cell; bone loss; cell type; cytokine; defense response; experimental study; human disease; macrophage; microbial; microbiota; monocyte; neutralizing antibody; novel; oral bacteria; osteoclastogenesis; periodontopathogen; peripheral blood; receptor; uptake

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 mouse bone cells and macrophages through engagement of the innate immune system, specifically through Toll Receptor 2 (TLR2). We also have recently discovered a new class of glycine lipids in P. gingivalis that also engage TLR2. The glycine class called Lipid 342 engages TLR2 but contains only one acyl chain, indicating that it is the smallest TLR2 agonist yet described. Understanding how glycine lipids promote TLR2-dependent cellular effects is relevant specifically to the reported effects of P. gingivalis on periodontal bone loss in experimental animals. P. gingivalis glycine lipids are unusual in that they can be produced from serine lipids when exposed to primary cultures of mouse bone marrow macrophages and Lipid 342 can be produced from another glycine lipid, Lipid 567, when treated with phospholipase A2 (PLA2). Of note, chronic inflammation is associated with increased expression of PLA2 which results in elevated prostaglandin levels within chronically inflamed tissues. This application proposes to quantify the uptake and hydrolysis of serine and glycine lipids in human gingival cells including epithelial, fibrobast and macrophages. Next, we will evaluate the capacity of these lipid classes to engage TLR2 and its co-receptor in primary cultures of the human gingival cells. Finally, we will evaluate the capacity of these lipid classes to promote osteoclast formation from human macrophages. Human macrophages will be differentiated from peripheral blood monocytes by treatment with M-CSF and osteoclast formation will be evaluated after treatment with the glycine of serine lipid classes. We will also treat M-CSF differentiated macrophages with the various classes of glycine and serine lipids and evaluate the capacity of macrophage culture supernatants to promote osteoclast formation. The experiments summarized in this proposal will clarify how P. gingivalis promotes TLR2-dependent bone loss in periodontal diseases.

牙龈卟啉单胞菌是一种牙周病病原体，与牙周炎的发生和发展有关。 成人慢性牙周炎。我们最近证明，这种生物体产生两种新的 类丝氨酸脂质抑制骨细胞功能和激活巨噬细胞释放重要的 细胞因子这些丝氨酸脂质中的至少一种还介导其对小鼠骨细胞的作用， 巨噬细胞通过参与先天免疫系统，特别是通过Toll受体2 （TLR2）。我们最近还在牙龈卟啉单胞菌中发现了一类新的甘氨酸脂质， 启动TLR 2称为脂质342的甘氨酸类与TLR 2结合，但仅含有一个酰基链， 这表明它是迄今为止所描述的最小的TLR 2激动剂。了解甘氨酸脂质如何促进 TLR 2依赖性细胞效应与牙龈卟啉单胞菌对牙龈卟啉单胞菌的作用有关。 实验动物的牙周骨丢失。牙龈卟啉单胞菌甘氨酸脂质是不寻常的，因为它们可以 当暴露于小鼠骨髓巨噬细胞的原代培养物时， 当用磷脂酶处理时，脂质342可以由另一种甘氨酸脂质脂质567产生 A2（PLA2）。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。本申请建议 量化人牙龈细胞中丝氨酸和甘氨酸脂质的摄取和水解，包括 上皮细胞、成纤维细胞和巨噬细胞。接下来，我们将评估这些脂质类的能力， 在人牙龈细胞的原代培养物中接合TLR 2及其共受体。最后我们将 评价这些脂质类促进人巨噬细胞破骨细胞形成的能力。 通过用M-CSF处理，人巨噬细胞将从外周血单核细胞分化 并在用丝氨酸脂质类的甘氨酸处理后评价破骨细胞形成。我们 还将用各种类型的甘氨酸和丝氨酸脂质处理M-CSF分化的巨噬细胞 并评价巨噬细胞培养上清液促进破骨细胞形成的能力。的 本提案中总结的实验将阐明牙龈卟啉单胞菌如何促进TLR 2依赖性骨 牙周病的危害

项目成果

Metabolism of serine/glycine lipids by human gingival cells in culture.

培养中的人牙龈细胞对丝氨酸/甘氨酸脂质的代谢。

• DOI: 10.1111/omi.12439
• 发表时间: 2023
• 期刊: Molecular oral microbiology
• 影响因子: 3.7
• 作者: Guido,TylerM;Ratcliffe,SamuelD;Rahmlow,Amanda;Zambrello,MatthewA;Provates,AnthonyA;Clark,RobertB;Smith,MichaelB;Nichols,FrankC
• 通讯作者: Nichols,FrankC

In Situ Raman Study of Neurodegenerated Human Neuroblastoma Cells Exposed to Outer-Membrane Vesicles Isolated from Porphyromonas gingivalis.

• DOI: 10.3390/ijms241713351
• 发表时间: 2023-08-28
• 期刊: International journal of molecular sciences
• 影响因子: 5.6