Histones, DNA, and Citrullination Promote Neutrophil Extracellular Trap Inflammation by Regulating the Localization and Activation of TLR4
Histones, DNA, and Citrullination Promote Neutrophil Extracellular Trap Inflammation by Regulating the Localization and Activation of TLR4
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DOI：
10.1016/j.celrep.2020.107602
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发表时间：
2020-05-05
期刊：
影响因子：
8.8
通讯作者：
Papayannopoulos, Venizelos
中科院分区：
文献类型：
--
作者：
Tsourouktsoglou, Theodora-Dorita;Warnatsch, Annika;Papayannopoulos, Venizelos
中性粒细胞胞外陷阱（NET）通过诱导促炎细胞因子促进动脉粥样硬化，但其潜在机制仍不清楚。 NET DNA 具有免疫原性，但考虑到 NET 组蛋白的细胞毒性，尚不清楚它如何激活细胞而不杀死细胞。在这里，我们发现组蛋白、DNA、瓜氨酸化和片段化协同作用，将炎症驱动至组蛋白细胞毒性阈值以下。在低浓度下，核小体会诱导细胞因子，但在高浓度下会在细胞因子产生之前杀死细胞。组蛋白和 DNA 之间的协同作用对于亚致死信号传导至关重要，并且依赖于组蛋白和 DNA 的不同作用。组蛋白结合并激活 TLR4，而 DNA 将 TLR4 招募到含有组蛋白的内体中。瓜氨酸化对于 NETosis 来说是可有可无的，但会增强组蛋白介导的信号传导。一致地，染色质阻断或 PAD4 缺乏可减少动脉粥样硬化。表达 GFP 标记组蛋白（可阻断 TLR4 结合）的受感染小鼠的炎症也有所减轻。因此，染色质通过使用具有不同功能的信号的协同机制促进无菌疾病和感染中的炎症。
Neutrophil extracellular traps (NETs) promote atherosclerosis by inducing proinflammatory cytokines, but the underlying mechanism remains unknown. NET DNA is immunogenic, but given the cytotoxicity of NET histones, it is unclear how it activates cells without killing them. Here, we show that histones, DNA, citrullination, and fragmentation synergize to drive inflammation below the histone cytotoxicity threshold. At low concentrations, nucleosomes induce cytokines, but high concentrations kill cells before cytokines are produced. The synergy between histones and DNA is critical for sub-lethal signaling and relies on distinct roles for histones and DNA. Histones bind and activate TLR4, whereas DNA recruits TLR4 to histone-containing endosomes. Citrullination is dispensable for NETosis but potentiates histone-mediated signaling. Consistently, chromatin blockade or PAD4 deficiency reduces atherosclerosis. Inflammation is also reduced in infected mice expressing GFP-tagged histones that block TLR4 binding. Thus, chromatin promotes inflammation in sterile disease and infection via synergistic mechanisms that use signals with distinct functions.