Regulation of neutrophil apoptosis throught the pleiotropic receptor FPR2

通过多效性受体 FPR2 调节中性粒细胞凋亡

• 批准号: 402286-2011
• 负责人: Filep, Janos
• 金额: $ 2.19万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=550856
• 关键词: Regulation; neutrophil; apoptosis; throught; pleiotropic

Neutrophil granulocytes constitute the first line of defense against infection, but are also capable of inflicting unwanted tissue damage. Recent results from our laboratories contributed to the identification of programmed cell death (apoptosis) of neutrophils as an important control point in the resolution of inflammation. Since neutrophils are exposed to multiple mediators in the inflammatory microenvironment, their fate ultimately depends upon the balance between survival and death-promoting (pro-apoptotic) signalling circuits. Human neutrophils express the receptor named FPR2/ALX, which binds an unusually large number of structurally unrelated molecules (ligands), including the acute-phase reactant serum amyloid A (SAA), the anti-inflammatory lipids lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4, the glucocorticoid-regulated protein annexin A1, and the bacteria-killing peptide CAP18/LL-37. Little is known about how this receptor recognizes and differentially responds to various ligands in regard with life and death decisions. In the current proposal we address this gap in our knowledge. We will study the impact and hierarchy among the above-mentioned ligands on apoptosis of human neutrophils, HL-60 cells (a model system in which genes can easily be manipulated) and neutrophils isolated from genetically modified mice lacking certain signalling molecules. We will combine immunological, biochemical, cell biology and molecular biology techniques to explore the underlying molecular mechanisms. Using mouse models of acute inflammation, we will investigate whether ligand hierarchy translates into modulation of the longevity of neutrophils and outcome of inflammation in vivo.

中性粒细胞是抵御感染的第一道防线，但也能造成不必要的组织损伤。我们实验室的最新结果有助于确定中性粒细胞的程序性细胞死亡(凋亡)是炎症消退的重要控制点。由于中性粒细胞暴露在炎症微环境中的多种介质中，它们的命运最终取决于生存和促死亡(促凋亡)信号通路之间的平衡。人类中性粒细胞表达名为FPR2/ALX的受体，该受体结合了大量结构无关的分子(配体)，包括急性时相反应物血清淀粉样蛋白A(SAA)、抗炎脂质LXA4(LXA4)和阿司匹林触发的15-epi-LXA4、糖皮质激素调节蛋白Annexin A1和杀菌肽CAP18/LL-37。关于这种受体如何识别和差异反应不同的配体，关于生死决定，人们知之甚少。在目前的提案中，我们解决了我们知识中的这一差距。我们将研究上述配体对人类中性粒细胞、HL-60细胞(一种易于操纵基因的模型系统)和从缺乏某些信号分子的转基因小鼠分离的中性粒细胞凋亡的影响和等级。我们将结合免疫学、生化、细胞生物学和分子生物学技术来探索潜在的分子机制。利用小鼠急性炎症模型，我们将研究配体等级是否在体内转化为调节中性粒细胞的寿命和炎症结果。