NTPDase1 governs P2X7-dependent functions in murine macrophages.
NTPDase1 governs P2X7-dependent functions in murine macrophages.
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DOI：
10.1002/eji.200939741
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发表时间：
2010-05
影响因子：
5.4
通讯作者：
Sevigny, Jean
中科院分区：
文献类型：
--
作者：
Levesque, Sebastien A.;Kukulski, Filip;Enjyoji, Keiichi;Robson, Simon C.;Sevigny, Jean
P2X7受体是多蛋白炎症体复合体中的一种三磷酸腺苷门控离子通道。到目前为止，对巨噬细胞中P2X7效应功能的调控知之甚少。在这里，我们发现NTPDase1/CD39是小鼠腹膜巨噬细胞表达的主要胞外核苷酸酶，它调节这些细胞中依赖于P2X7的反应。从NTPDase1基因缺失的小鼠分离的巨噬细胞(Entpd1−/−)与野生型巨噬细胞(Entpd1+/+)相比，缺乏所有ADPase和大部分ATPase活性。与Entpd1+/+细胞相比，暴露于毫摩尔浓度三磷酸腺苷的Entpd1−/−巨噬细胞更容易发生细胞死亡，经TLR2或TLR4刺激后释放更多的IL-1β和IL-18，并更有效地掺入荧光染料Yo-Pro-1(提示孔道形成增加)。与这些观察一致的是，NTPDase1在合成后调节与P2X7相关的IL-1β的释放，这一过程独立于Caspase-1的细胞因子成熟，并且在此之前发生。在气囊炎模型中，NTPDase1还能抑制体内IL-1β的释放。与Entpd1+/+小鼠相比，注射内毒素的Entpd1−/−小鼠的渗出液中IL-1β水平显著升高。综上所述，我们的研究表明，NTPDase1/CD39在控制依赖于P2X7的巨噬细胞反应中起关键作用。
P2X7 receptor is an ATP-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. Here, we show that NTPDase1/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X7-dependent responses in these cells. Macrophages isolated from NTPDase1-null mice (Entpd1−/−) were devoid of all ADPase and most ATPase activities when compared to wild type macrophages (Entpd1+/+). Entpd1−/− macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL-1β 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 P2X7-associated IL-1β release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase-1. NTPDase1 also inhibited IL-1β release in vivo in the air pouch inflammatory model. Exudates of LPS-injected Entpd1−/− mice had significantly higher IL-1β levels when compared to Entpd1+/+ mice. Taken together, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X7-dependent macrophage responses.
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影响因子：
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作者：
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