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Inhibition of neutrophil apoptosis by ATP is mediated by the P2Y(11) receptor

Research output: Contribution to journalArticlepeer-review

  • Kathryn R. Vaughan
  • Leanne Stokes
  • Lynne R. Prince
  • Helen M. Marriott
  • Sabine Meis
  • Matthias U. Kassack
  • Colin D. Bingle
  • Ian Sabroe
  • Annmarie Surprenant
  • Moira K. B. Whyte

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)8544-8553
Number of pages10
JournalJournal of Immunology
Volume179
Issue number12
Publication statusPublished - 15 Dec 2007

Abstract

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 P2Y(11) receptor and inhibition of P2Y(11) 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 P2Y(11), without effects on constitutive apoptosis. Specific targeting of P2Y(11), could retain key immune functions of neutrophils but reduce the injurious effects of increased neutrophil longevity during inflammation.

    Research areas

  • P2X(7) NUCLEOTIDE RECEPTOR, DEPENDENT PROTEIN-KINASE, PROGRAMMED CELL-DEATH, PHOSPHOLIPASE-C, GRANULOCYTIC DIFFERENTIATION, ADENOSINE-TRIPHOSPHATE, ADENINE-NUCLEOTIDES, ENDOTHELIAL-CELLS, AGING NEUTROPHILS, EXTRACELLULAR ATP

ID: 17166175