The novel neutrophil differentiation marker phosphatidylglucoside is involved in Fas-dependent apoptosis

抄録

A new type of glycolipid, phosphatidylglucoside (PtdGlc), first identified as a component of lipid rafts in the human HL-60 leukemia cell line, has also been detected in human neutrophils during maturation. We show here that PtdGlc forms functional domains different from lactosylceramide (LacCer)-enriched lipid rafts and initiates neutrophil apoptosis via Fas-dependent death signaling. Among the human peripheral blood leukocytes and monocyte-derived dendritic cells (DCs), only neutrophils show high surface expression of PtdGlc, whereas LacCer is expressed on the surfaces of neutrophils, macrophages and DCs. LacCer couples with the Src family kinase Lyn, forming lipid rafts on plasma membranes, and mediates neutrophil chemotaxis, phagocytosis and superoxide generation, whereas PtdGlc does not mediate these functions. In contrast, PtdGlc but not LacCer is involved in neutrophil apoptosis. These observations suggest that PtdGlc and LacCer form distinct lipid domains on the plasma membrane. In addition, PtdGlc-mediated apoptosis was inhibited by specific inhibitors of caspases 8, 9 and 3, but not by the Src family kinase inhibitor PP1, the PI3 kinase inhibitor LY294002 or catalase. PtdGlc colocalized with Fas on neutrophil plasma membranes, and both the anti-PtdGlc antibody DIM21 and the agonist anti-Fas antibody B-10 induced the formation of large Fas-colocalized clusters of PtdGlc on plasma membranes. Furthermore, the antagonist anti-Fas antibody ZB4 significantly inhibited DIM21-induced neutrophil apoptosis. These results suggest that PtdGlc is specifically expressed on neutrophils and mediates activities of these cells, and that the Fas-associated death signal may be involved in PtdGlc-mediated apoptosis.