Inhibition of neutrophil apoptosis by ATP is mediated by the P2Y11 receptor.
Neutrophils undergo rapid constitutive apoptosis that is delayed by a range of pathogen- and host-derived inflammatory mediators. We have investigated the ability of the nucleotide ATP, to which neutrophils are exposed both in the circulation and at sites of inflammation, to modulate the lifespan of human neutrophils. We found that physiologically relevant concentrations of ATP cause a concentration-dependent delay of neutrophil apoptosis (assessed by morphology, annexin V/To-Pro3 staining, and mitochondrial membrane permeabilization). We found that even brief exposure to ATP (10 min) was sufficient to cause a long-lasting delay of apoptosis and showed that the effects were not mediated by ATP breakdown to adenosine. The P2 receptor mediating the antiapoptotic actions of ATP was identified using a combination of more selective ATP analogs, receptor expression studies, and study of downstream signaling pathways. Neutrophils were shown to express the P2Y11 receptor and inhibition of P2Y11 signaling using the antagonist NF157 abrogated the ATP-mediated delay of neutrophil apoptosis, as did inhibition of type I cAMP-dependent protein kinases activated downstream of P2Y11, without effects on constitutive apoptosis. Specific targeting of P2Y11 could retain key immune functions of neutrophils but reduce the injurious effects of increased neutrophil longevity during inflammation.
Academic Unit of Respiratory Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, UK.
Kathryn R
KR
Vaughan
Leanne
L
Stokes
Lynne R
LR
Prince
Helen M
HM
Marriott
Sabine
S
Meis
Matthias U
MU
Kassack
Colin D
CD
Bingle
Ian
I
Sabroe
Annmarie
A
Surprenant
Moira K B
MK
Whyte
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013498:Suramin / Q000031:analogs & derivatives / Q000494:pharmacology
C526891:NF157 compound; C109734:P2RY11 protein, human; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D013498:Suramin; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium