Cutting edge: Lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages

Lipoxins (LX) are lipoxygenase-derived eicosanoids generated during inflamm ation, LX inhibit polymorphonuclear neutrophil (PMN) chemotaxis and adhesio n and are putative braking signals for PMN-mediated tissue injury. In this study, we report that LXA(4) promotes another important step in the resolut ion phase of inflammation, namely, phagocytosis; of apoptotic PMN by monocy te-derived macrophages (M phi). LXA(4) triggered rapid, concentration-depen dent uptake of apoptotic PMN. This bioactivity was shared by stable synthet ic LXA(4) analogues (picomolar concentrations) but not by other eicosanoids tested. LXA(4)-triggered phagocytosis did not provoke IL-8 or monocyte che moattractant protein-1 release. LXA(4)-induced phagocytosis was attenuated by anti-CD36, alpha(v)beta(3), and CD18 mAbs. LXA(4)-triggered PMN uptake w as inhibited by pertussis toxin and by 8-bromo-cAMP and was mimicked by Rp- cAMP, a protein kinase A inhibitor. LXA(4) attenuated PGE(2)-stimulated pro tein kinase A activation in M phi. These results suggest that LXA(4) is an endogenous stimulus for PMN clearance during inflammation and provide a nov el rationale for using stable synthetic analogues as anti-inflammatory comp ounds in vivo.