The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release
The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release
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DOI：
10.1189/jlb.3hi0814-393r
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发表时间：
2016-01-01
影响因子：
5.5
通讯作者：
Okamura, Yasushi
中科院分区：
文献类型：
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作者：
Okochi, Yoshifumi;Aratani, Yasuaki;Okamura, Yasushi
中性粒细胞胞吐对宿主防御和炎症起着至关重要的作用。中性粒细胞含有4种颗粒，其胞吐释放受到不同程度的调节。已知这种胞吐作用是由不同的介质驱动的，包括钙和核苷酸，但确切的分子机制在很大程度上仍不清楚。在本研究中，我们发现电压门控质子(Hv)通道对于中性粒细胞中的亲天青颗粒的适当释放是必要的。在PMA和Ig G对NADPH氧化酶的激活作用上，Hvcn1基因敲除小鼠的中性粒细胞比WT细胞分泌更多的MPO和弹性蛋白酶。相反，在这些细胞中，富含特定颗粒的LTF的释放并没有增加。在Hv1/VSOP缺乏的中性粒细胞中，亲天青颗粒的过量释放可以通过抑制NADPH氧化酶活性来抑制，部分地被钾离子载体伐林霉素所抑制。此外，Hv1/VSOP缺陷小鼠在白色念珠菌鼻腔感染后表现出比WT小鼠更严重的肺部炎症。这些发现表明，Hv通道通过部分抑制质膜上增加的正电荷以及中性粒细胞内NADPH氧化酶的激活而特异性地抑制亲天蓝颗粒的释放。
Neutrophil granule exocytosis is crucial for host defense and inflammation. Neutrophils contain 4 types of granules, the exocytotic release of which is differentially regulated. This exocytosis is known to be driven by diverse mediators, including calcium and nucleotides, but the precise molecular mechanism remains largely unknown. We show in the present study that voltage-gated proton (Hv) channels are necessary for the proper release of azurophilic granules in neutrophils. On activation of NADPH oxidase by PMA and IgG, neutrophils derived from Hvcn1 gene knockout mouse exhibited greater secretion of MPO and elastase than WT cells. In contrast, release of LTF enriched in specific granules was not enhanced in these cells. The excess release of azurophilic granules in Hv1/VSOP-deficient neutrophils was suppressed by inhibiting NADPH oxidase activity and, in part, by valinomycin, a potassium ionophore. In addition, Hv1/VSOP-deficient mice exhibited more severe lung inflammation after intranasal Candida albicans infection than WT mice. These findings suggest that the Hv channel acts to specifically dampen the release of azurophilic granules through, in part, the suppression of increased positive charges at the plasma membrane accompanied by the activation of NADPH oxidase in neutrophils.