Opposing regulation of neutrophil apoptosis through the formyl peptide receptor-like 1/lipoxin A4 receptor: implications for resolution of inflammation.
Neutrophils have a central role in innate immunity, and their programmed cell death and removal are critical to the optimal expression as well as to efficient resolution of inflammation. Human neutrophils express the pleiotropic receptor formyl peptide receptor-like 1/lipoxin A4 (LXA(4)) receptor that binds a variety of ligands, including the acute-phase reactant serum amyloid A (SAA), the anti-inflammatory lipids LXA(4) and aspirin-triggered 15-epi-LXA(4) (ATL), and the glucocorticoid-inducible protein annexin 1. In addition to regulation of neutrophil activation and recruitment, these ligands have a profound influence on neutrophil survival and apoptosis with contrasting actions, mediating aggravation or resolution of the inflammatory response. Thus, annexin 1 accelerates, whereas SAA rescues human neutrophils from constitutive apoptosis by preventing mitochondrial dysfunction and subsequent activation of caspase-3. Furthermore, ATL overcomes the antiapoptosis signal from SAA and redirects neutrophils to caspase-mediated cell death. We review recent developments about the molecular basis of these actions and suggest a novel mechanism by which aspirin promotes resolution of acute inflammation and tissue injury.
El Kebir
Driss
D
Research Center, Maisonneuve-Rosemont Hospital, 5415 Boulevard de l'Assomption, Montréal, QC, Canada, H1T 2M4.
József
Levente
L
Filep
János G
JG
D017305:Annexin A1 / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001241:Aspirin / Q000494:pharmacology; D006801:Humans; D044045:Lipoxins / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000378:metabolism
D017305:Annexin A1; D051017:Apoptosis Regulatory Proteins; C105101:FPR2 protein, human; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D000685:Serum Amyloid A Protein; C040527:lipoxin A4; D001241:Aspirin