Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
J Cell Biol. 2010 Nov 1;191(3):677-91. doi: 10.1083/jcb.201006052. Epub 2010 Oct 25.
Neutrophils release decondensed chromatin termed neutrophil extracellular traps (NETs) to trap and kill pathogens extracellularly. Reactive oxygen species are required to initiate NET formation but the downstream molecular mechanism is unknown. We show that upon activation, neutrophil elastase (NE) escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. Subsequently, myeloperoxidase synergizes with NE in driving chromatin decondensation independent of its enzymatic activity. Accordingly, NE knockout mice do not form NETs in a pulmonary model of Klebsiella pneumoniae infection, which suggests that this defect may contribute to the immune deficiency of these mice. This mechanism provides for a novel function for serine proteases and highly charged granular proteins in the regulation of chromatin density, and reveals that the oxidative burst induces a selective release of granular proteins into the cytoplasm through an unknown mechanism.
中性粒细胞会释放去凝聚的染色质，称为中性粒细胞胞外诱捕网（NETs），从而在细胞外捕获和杀死病原体。活性氧是启动 NET 形成所必需的，但下游的分子机制尚不清楚。我们发现，中性粒细胞弹性蛋白酶（NE）在激活后会从嗜天青颗粒中逸出，并转移到细胞核内，在那里它会部分降解特定的组蛋白，促进染色质去凝聚。随后，髓过氧化物酶（MPO）与 NE 协同作用，在不依赖其酶活性的情况下驱动染色质去凝聚。因此，中性粒细胞弹性蛋白酶基因敲除小鼠在肺炎克雷伯菌感染的肺部模型中不会形成 NETs，这表明这种缺陷可能导致这些小鼠的免疫缺陷。该机制为丝氨酸蛋白酶和带高电荷的颗粒蛋白在调节染色质密度方面提供了新的功能，并揭示了氧化爆发通过未知机制诱导颗粒蛋白选择性释放到细胞质中。
