Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages.
Lipoxins (LX) are lipoxygenase-derived eicosanoids generated during inflammation. LX inhibit polymorphonuclear neutrophil (PMN) chemotaxis and adhesion and are putative braking signals for PMN-mediated tissue injury. In this study, we report that LXA4 promotes another important step in the resolution phase of inflammation, namely, phagocytosis of apoptotic PMN by monocyte-derived macrophages (Mphi). LXA4 triggered rapid, concentration-dependent uptake of apoptotic PMN. This bioactivity was shared by stable synthetic LXA4 analogues (picomolar concentrations) but not by other eicosanoids tested. LXA4-triggered phagocytosis did not provoke IL-8 or monocyte chemoattractant protein-1 release. LXA4-induced phagocytosis was attenuated by anti-CD36, alphavbeta3, and CD18 mAbs. LXA4-triggered PMN uptake was inhibited by pertussis toxin and by 8-bromo-cAMP and was mimicked by Rp-cAMP, a protein kinase A inhibitor. LXA4 attenuated PGE2-stimulated protein kinase A activation in Mphi. These results suggest that LXA4 is an endogenous stimulus for PMN clearance during inflammation and provide a novel rationale for using stable synthetic analogues as anti-inflammatory compounds in vivo.
Godson
C
C
Centre for Molecular Inflammation and Vascular Research, Mater Misericordiae Hospital, Department of Medicine, Dublin, Ireland. cgodson@mater.ie
Mitchell
S
S
Harvey
K
K
Petasis
N A
NA
Hogg
N
N
Brady
H R
HR
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D044045:Lipoxins; D008264:Macrophages / Q000276:immunology*; D018716:Molecular Mimicry; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; C040527:lipoxin A4; D017868:Cyclic AMP-Dependent Protein Kinases