Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 40, Issue 5, Pages 1473-1485Publisher
WILEY
DOI: 10.1002/eji.200939741
Keywords
ATP-induced death; CD39; IL-1 beta; Macrophage; Nucleoside triphosphate diphosphohydrolase 1
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Funding
- Canadian Institutes of Health Research (CIHR)
- Arthritis Society of Canada
- NIH [HL08, HL094400]
- Fond Hydro-Quebec
- Fonds de la Recherche en Sante du Quebec (FRSQ)
- CIHR/Wyeth Pharmaceuticals
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P2X(7) receptor is an adenosine triphosphate (ATP)-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X(7) effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X(7)-dependent responses in these cells. Macrophages isolated from NTPDase1-null mice (Entpd1(-/-)) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1(+/+)). Entpd1(-/-) macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL-1 beta and IL-18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo-Pro-1 more efficiently (suggestive of increased pore formation) than Entpd1(+/+) cells. Consistent with these observations, NTPDase1 regulated P2X(7)-associated IL-1 beta release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase-1. NTPDase1 also inhibited IL-1 beta release in vivo in the air pouch inflammatory model. Exudates of LPS-injected Entpd1(-/-) mice had significantly higher IL-1 beta levels when compared with Entpd1(+/+) mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X(7)-dependent macrophage responses.
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