ATP secreted by endothelial cells blocks CX₃CL 1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y₁₁ receptor activation.
Endothelial cells (ECs) represent a major source of actively secreted adenosine triphosphate (ATP). Natural killer (NK) cells can mediate vascular injury in several pathologic conditions, including cytomegalovirus infection and vascular leak syndrome. We studied NK-cell expression of P2 receptors and the role of these nucleotide receptors in the regulation of endothelial-NK cell cross-talk. NK cells from healthy subjects expressed P2Y(₁,₂,₄,₆,₁₁,₁₂,₁₃,₁₄) and P2X(₁,₄,₅,₆,₇) receptors. NK cells stimulated with ATP, but not uridine triphosphate, increased intracellular Ca²(+) and chemokinesis. Moreover, ATP, but not uridine triphosphate, inhibited NK chemotaxis in response to CX₃CL1, whereas chemotaxis to CXCL12 was increased. CX₃CL1 elicited killing of human umbilical vein ECs and human coronary artery ECs by NK cells. However, in the presence of ATP, CX₃CL1 failed to stimulate killing of ECs. Such inhibitory effect was lost on exogenous addition of the ATP-hydrolyzing enzyme apyrase or by pharmacologic inhibition of the P2Y₁₁R, and correlated with increased intracellular cyclic adenosine monophosphate concentrations induced by ATP or other P2Y₁₁R agonists, including NAD(+). Extracellular ATP regulates NK-cell cytotoxicity via P2Y₁₁R activation, protecting ECs from CX₃CL1-elicited NK cell-mediated killing. These findings point out the P2Y₁₁R as a potential target for pharmacologic intervention aimed at reducing NK-mediated vascular injury.
Gorini
Stefania
S
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Pisana, Rome, Italy.
Callegari
Giulia
G
Romagnoli
Giulia
G
Mammi
Caterina
C
Mavilio
Domenico
D
Rosano
Giuseppe
G
Fini
Massimo
M
Di Virgilio
Francesco
F
Gulinelli
Sara
S
Falzoni
Simonetta
S
Cavani
Andrea
A
Ferrari
Davide
D
la Sala
Andrea
A
D000255:Adenosine Triphosphate / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000276:immunology*; D002633:Chemotaxis; D000242:Cyclic AMP / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000276:immunology*; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000276:immunology; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000276:immunology
D054428:Chemokine CX3CL1; C109734:P2RY11 protein, human; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D002118:Calcium