PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.
PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.
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DOI：
10.1084/jem.20100239
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发表时间：
2010-08-30
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
中性粒细胞通过形成高度解缩的染色质结构来捕获和杀灭细菌，称为中性粒细胞胞外陷阱(NETs)。我们先前报道了组蛋白的高瓜氨酸化与网络形成过程中染色质的解缩有关。然而，PAD4在网络介导的细菌捕获和杀灭中的作用还没有得到测试。在这里，我们使用PAD4基因敲除的小鼠来证明PAD4对于网络介导的抗菌功能是必不可少的。与Pad 4+/+中性粒细胞不同，Pad 4−/−中性粒细胞在趋化因子刺激或与细菌孵育后不能形成Net，缺乏Net杀菌能力。在坏死性筋膜炎的小鼠传染病模型中，由于缺乏网络形成，Pad 4−/−小鼠比Pad 4+/+小鼠更容易受到细菌感染。此外，我们还发现，瓜氨酸化降低了组蛋白和核小体的杀菌活性，这表明PAD4主要在染色质解缩形成Net的过程中发挥作用，而不是增加组蛋白介导的细菌杀灭。我们的结果确定了组蛋白高瓜氨酸化在细菌感染期间的先天免疫中的作用。
Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation. However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. Unlike PAD4+/+ neutrophils, PAD4−/− neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious disease model of necrotizing fasciitis, PAD4−/− mice are more susceptible to bacterial infection than PAD4+/+ mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.
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