Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells
Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells
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DOI：
10.4049/jimmunol.1800159
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发表时间：
2019-10-15
影响因子：
4.4
通讯作者：
Fadeel, Bengt
中科院分区：
文献类型：
--
作者：
Lazzaretto, Beatrice;Fadeel, Bengt
由核DNA、组蛋白和颗粒蛋白组成的神经元细胞外陷阱（NETs）参与了病原体的细胞外杀伤。过多的NET形成与几种非感染性病理状态有关。因此，NET的处置对于防止由于NET在细胞外环境中的持续存在而导致的无意影响是重要的。在这项研究中，我们研究了由新鲜分离的PMA刺激的原代人中性粒细胞释放的NET与原代人单核细胞衍生的巨噬细胞或树突状细胞（DC）的相互作用。NET被巨噬细胞内化，去除蛋白质成分防止了NET的吞噬，而与LL-37的复合恢复了"裸"（无蛋白质）NET的摄取。NET也被发现抑制细菌LPS诱导的DC成熟。在NET与巨噬细胞或DC相互作用后，通过使用多重阵列进行细胞因子分析，发现单独的NET是非炎症性的，而在LPS存在下注意到免疫调节作用，IL-1 β分泌显著上调，并且在两种细胞类型中显著抑制其他LPS诱导的因子，包括血管内皮生长因子（VEGF）。此外，NET的巨噬细胞消化依赖于TREX1（也称为DNaseIII），但不依赖于DNaseII，而细胞外DNase1L3介导的NET降解在DC中观察到。总的来说，这些发现揭示了NET和吞噬细胞之间的相互作用，并提供了关于NET清除的新见解，先天免疫的双刃剑。
Neutrophil extracellular traps (NETs) composed of nuclear DNA associated with histones and granule proteins are involved in the extracellular killing of pathogens. Excessive NET formation has been implicated in several noninfectious pathological conditions. The disposal of NETs is, therefore, important to prevent inadvertent effects resulting from the continued presence of NETs in the extracellular environment. In this study, we investigated the interaction of NETs released by freshly isolated, PMA-stimulated primary human neutrophils with primary human monocyte-derived macrophages or dendritic cells (DCs). NETs were internalized by macrophages, and removal of the protein component prevented engulfment of NETs, whereas complexation with LL-37 restored the uptake of "naked" (protein-free) NETs. NETs were also found to dampen the bacterial LPS-induced maturation of DCs. Cytokine profiling was conducted by using a multiplex array following the interaction of NETs with macrophages or DCs, and NETs alone were found to be noninflammatory, whereas immunomodulatory effects were noted in the presence of LPS with significant upregulation of IL-1 beta secretion, and a marked suppression of other LPS-induced factors including vascular endothelial growth factor (VEGF) in both cell types. Moreover, macrophage digestion of NETs was dependent on TREX1 (also known as DNaseIII), but not DNaseII, whereas extracellular DNase1L3-mediated degradation of NETs was observed for DCs. Collectively, these findings shed light on the interactions between NETs and phagocytic cells and provide new insights regarding the clearance of NETs, double-edged swords of innate immunity.