Ca2+ activation of cytosolic calpain induces the transition from apoptosis to necrosis in neutrophils with externalized phosphatidylserine
Ca2+ activation of cytosolic calpain induces the transition from apoptosis to necrosis in neutrophils with externalized phosphatidylserine
复制标题
DOI：
10.1189/jlb.0412212
复制
发表时间：
2013-01-01
影响因子：
5.5
通讯作者：
Hallett, M. B.
中科院分区：
文献类型：
--
作者：
Francis, R. J.;Kotecha, S.;Hallett, M. B.
在生理学上，凋亡的中性粒细胞在坏死之前被摄入。然而，摄入失败将导致中性粒细胞坏死和嗜中性粒细胞衍生的致病分子（如蛋白酶和水解酶）的不受调节的释放。因此，了解凋亡后坏死的机制显然很重要。在这里，我们监测了在体外的个人年龄的人中性粒细胞，细胞内钙离子和膜完整性的成像荧光探针的approximatic-to-necrotic的转变。这表明，坏死前老化的中性粒细胞与外部PS有一个显着升高的cytosolic-free Ca 2+水平。一个进一步的不受管制的Ca 2+流入PS外化中性粒细胞总是在坏死过渡之前。Ca 2+升高不是简单的老化的结果，PS外化是不均匀的类似年龄的中性粒细胞群体。PS-externalized中性粒细胞可以诱导进行实验性坏死，通过简单地升高胞浆Ca 2+进一步与离子霉素。这种效应仅在具有外化PS的中性粒细胞中观察到，并且与它们从血液中分离后的时间无关（即，体外老化）。由于钙蛋白酶-1抑制的药理学抑制显著降低了这种CAIN，因此得出结论，从坏死到坏死的转变是由PS外化中性粒细胞中Ca 2+过载引起的不受控制的钙蛋白酶激活的结果。J.利瓦克93：95-100; 2013.
Physiologically, apoptotic neutrophils are ingested before they undergo necrosis. However, failure of ingestion will lead to necrosis of neutrophils and the unregulated release of neutrophil-derived pathogenic molecules, such as protease and hydrolases. Understanding the mechanism of postapoptotic necrosis is thus clearly important. Here, we monitored the apoptotic-to-necrotic transition in individual-aged human neutrophils in vitro by imaging fluorescent probes for externalized PS, cytosolic Ca2+, and membrane integrity. This showed that prenecrotic-aged neutrophils with externalized PS had a significantly elevated cytosolic-free Ca2+ level. A further unregulated Ca2+ influx into PS-externalized neutrophils always preceded the necrotic transition. Ca2+ elevation was not simply a consequence of aging, as PS externalization was not uniform in similarly aged neutrophil populations. PS-externalized neutrophils could be induced to undergo necrosis experimentally by simply elevating cytosolic Ca2+ further with ionomycin. This effect was observed only in neutrophils that had externalized PS, and was independent of the time after their isolation from blood (i.e., in vitro age). As pharmacological inhibition of calpain-1 inhibition significantly reduced this CAIN, it was concluded that the apoptotic-to-necrotic transition was a consequence of uncontrolled calpain activation that resulted from Ca2+ overload in PS-externalized neutrophils. J. Leukoc. Biol. 93: 95-100; 2013.