Neutrophil extracellular trap cell death requires both autophagy and superoxide generation
Neutrophil extracellular trap cell death requires both autophagy and superoxide generation
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DOI：
10.1038/cr.2010.150
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发表时间：
2011-02-01
期刊：
影响因子：
44.1
通讯作者：
Vandenabeele, Peter
中科院分区：
文献类型：
--
作者：
Remijsen, Quinten;Vanden Berghe, Tom;Vandenabeele, Peter
中性粒细胞胞外陷阱（NETs）是细胞外染色质结构，可以捕获和降解微生物。它们产生于中性粒细胞激活了一种叫做NET细胞死亡或NETosis的细胞死亡程序。NETosis的激活已被证明涉及NADPH氧化酶活性，核膜和大多数颗粒膜的解体，核染色质的去浓缩和NETs的形成。我们报道，在肉豆蔻酸酯phorbol myristate acetate （PMA）刺激的中性粒细胞中，细胞内染色质去浓缩和NET的形成遵循自噬和超氧化物的产生，这两者都是介导PMA诱导的NETosis所必需的，并且彼此独立发生。缺乏NADPH氧化酶活性的慢性肉芽肿患者的中性粒细胞仍然表现出pma诱导的自噬。相反，pma诱导的NADPH氧化酶活性不受自噬药物抑制的影响。有趣的是，抑制自噬或NADPH氧化酶均可阻止细胞内染色质去浓缩，而去浓缩是NETosis和NET形成所必需的，并导致以细胞凋亡为特征的细胞死亡。这些结果表明，当自噬或NADPH氧化酶活性被阻止时，细胞凋亡可能作为NETosis的备份程序。
Neutrophil extracellular traps (NETs) are extracellular chromatin structures that can trap and degrade microbes. They arise from neutrophils that have activated a cell death program called NET cell death, or NETosis. Activation of NETosis has been shown to involve NADPH oxidase activity, disintegration of the nuclear envelope and most granule membranes, decondensation of nuclear chromatin and formation of NETs. We report that in phorbol myristate acetate (PMA)-stimulated neutrophils, intracellular chromatin decondensation and NET formation follow autophagy and superoxide production, both of which are required to mediate PMA-induced NETosis and occur independently of each other. Neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase activity, still exhibit PMA-induced autophagy. Conversely, PMA-induced NADPH oxidase activity is not affected by pharmacological inhibition of autophagy. Interestingly, inhibition of either autophagy or NADPH oxidase prevents intracellular chromatin decondensation, which is essential for NETosis and NET formation, and results in cell death characterized by hallmarks of apoptosis. These results indicate that apoptosis might function as a backup program for NETosis when autophagy or NADPH oxidase activity is prevented.