Ecto-nucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1/CD39) regulates neutrophil chemotaxis by hydrolyzing released ATP to adenosine
Ecto-nucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1/CD39) regulates neutrophil chemotaxis by hydrolyzing released ATP to adenosine
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DOI：
10.1074/jbc.m800039200
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发表时间：
2008-10-17
影响因子：
4.8
通讯作者：
Junger, Wolfgang G.
中科院分区：
文献类型：
--
作者：
Corriden, Ross;Chen, Yu;Junger, Wolfgang G.
多形核中性粒细胞在化学引诱剂（如肽n -甲酰基-甲硫基-亮基-苯丙氨酸）的刺激下释放ATP。释放的ATP和水解产物腺苷分别通过顺序激活嘌呤能核苷酸和腺苷受体来调节中性粒细胞的趋化性。在这里，我们发现外核苷三磷酸二磷酸水解酶1 （E-NTPDase1, CD39）是中性粒细胞水解释放的ATP和响应多种激动剂（n-甲酰基-蛋氨酸-亮氨酸-苯丙氨酸，白介素-8和C5a）的细胞迁移的关键酶。在趋化梯度刺激人中性粒细胞或分化的HL-60细胞时，E-NTPDase1在趋化过程中与极化细胞的前沿紧密结合。抑制E-NTPDase1会降低中性粒细胞的迁移速度，但不会降低它们检测梯度场方向的能力。对E-NTPDase1基因敲除小鼠的中性粒细胞的研究表明，体外和体内的趋化性也有类似的损伤。因此，E-NTPDase1通过促进细胞外ATP的水解，在调节中性粒细胞趋化性中发挥重要作用。
Polymorphonuclear neutrophils release ATP in response to stimulation by chemoattractants, such as the peptide N-formyl-methionyl-leucyl-phenylalanine. Released ATP and the hydrolytic product adenosine regulate chemotaxis of neutrophils by sequentially activating purinergic nucleotide and adenosine receptors, respectively. Here we show that that ecto-nucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1, CD39) is a critical enzyme for hydrolysis of released ATP by neutrophils and for cell migration in response to multiple agonists (N-formyl-methionyl-leucyl-phenylalanine, interleukin-8, and C5a). Upon stimulation of human neutrophils or differentiated HL-60 cells in a chemotactic gradient, E-NTPDase1 tightly associates with the leading edge of polarized cells during chemotaxis. Inhibition of E-NTPDase1 reduces the migration speed of neutrophils but not their ability to detect the orientation of the gradient field. Studies of neutrophils from E-NTPDase1 knockout mice reveal similar impairments of chemotaxis in vitro and in vivo. Thus, E-NTPDase1 plays an important role in regulating neutrophil chemotaxis by facilitating the hydrolysis of extracellular ATP.