Regulation of neutrophil apoptosis throught the pleiotropic receptor FPR2

中性粒细胞构成抵抗感染的第一道防线，但也能够造成不必要的组织损伤。我们实验室的最新结果有助于将中性粒细胞的程序性细胞死亡（凋亡）鉴定为炎症消退的重要控制点。由于中性粒细胞暴露于炎症微环境中的多种介质，它们的命运最终取决于存活和促死亡（促凋亡）信号通路之间的平衡。人类中性粒细胞表达名为FPR 2/ALX的受体，其结合异常大量的结构上不相关的分子（配体），包括急性期反应物血清淀粉样蛋白A（SAA）、抗炎脂质脂氧素A4（LXA 4）和阿司匹林触发的15-epi-LXA 4、糖皮质激素调节蛋白膜联蛋白A1和杀菌肽CAP 18/LL-37。很少有人知道这种受体如何识别和不同的各种配体在生死决定方面的反应。在目前的建议中，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中性粒细胞、HL-60细胞（一种基因易于操纵的模型系统）和从缺乏某些信号分子的转基因小鼠中分离的中性粒细胞凋亡的影响和层次。我们将结合联合收割机、免疫学、生物化学、细胞生物学和分子生物学技术来探索潜在的分子机制。使用急性炎症的小鼠模型，我们将研究配体等级是否转化为中性粒细胞寿命的调节和体内炎症的结果。 这项研究的结果将进一步加深我们对FPR 2/ALX激活如何整合决定中性粒细胞命运的相反信号的分子机制的理解。这些知识可能为设计新的治疗方法提供合理的基础，这些方法旨在诱导炎症组织中的中性粒细胞凋亡，以增强炎症的消退。

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. The results from this study will further our understanding of the molecular mechanisms how activation of FPR2/ALX integrates opposing signals that determine the fate of neutrophils. This knowledge may provide a rational basis for designing novel therapeutic approaches aimed at induction of neutrophil apoptosis in inflamed tissues to enhance the resolution of inflammation.