Serum amyloid A inhibits apoptosis of human neutrophils via a P2X7-sensitive pathway independent of formyl peptide receptor-like 1.
Neutrophil apoptosis is important for the termination of inflammatory reactions, in that it ensures placid clearance of these potently cytotoxic cells. Various proinflammatory cytokines delay neutrophil apoptosis, which may result in accumulation of these cells, sometimes accompanied by tissue destruction, potentially leading to various inflammatory disease states. Rheumatoid arthritis (RA) is characterized frequently by elevated levels of the acute-phase reactant serum amyloid A (SAA) in circulation and in tissues. SAA is emerging as a cytokine-like molecule with the ability to activate various proinflammatory processes, many of which involve signaling via the formyl peptide receptor-like 1 (FPRL1). In this study, we show that SAA, purified from plasma from RA patients or in recombinant form, suppressed apoptosis of human neutrophils. Blocking FPRL1 did not lessen the antiapoptotic effects of SAA, implying the action of a receptor distinct from FPRL1. In contrast, antagonists of the nucleotide receptor P2X7 abrogated the antiapoptotic effect of SAA completely but did not block intracellular calcium transients evoked by SAA stimulation. Based on these results and also the finding that blocking P2X7 inhibited antiapoptotic actions of unrelated stimuli (LPS and GM-CSF), we propose that P2X7 is a general mediator of antiapoptotic signaling in neutrophils rather than a bona fide SAA receptor.
Christenson
Karin
K
Department of Rheumatology and Inflammation Research, Göteborg University, Guldhedsgatan 10, 413 46 Göteborg, Sweden.
Björkman
Lena
L
Tängemo
Carolina
C
Bylund
Johan
J
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D012680:Sensitivity and Specificity; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000494:pharmacology*
C105101:FPR2 protein, human; C546468:P2RX7 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000685:Serum Amyloid A Protein