Regulation of neutrophil apoptosis throught the pleiotropic receptor FPR2

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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.