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Abstract：
Gold nanoparticles (AuNPs) are extensively utilized in biomedical fields. However, their potential interaction with host cells has not been comprehensively elucidated. In this study, we demonstrated a size-dependent effect of AuNPs to synergize with bacterial lipopolysaccharide (LPS) in promoting neutrophil extracellular traps (NETs) release in human peripheral neutrophils. Mechanistically, LPS was more efficient to contact with 10 nm AuNPs and promote their uptake in neutrophils compared to 40 and 100 nm AuNPs, leading to a synergistic upregulation of class A scavenger receptor (SRA) which mediated AuNPs uptake and triggered activation of extracellular regulated protein kinase (ERK) and p38. Blocking SRA or inhibiting ERK and p38 activation remarkably abrogated the effect of AuNPs and LPS to induce NETs formation. Further experiments demonstrated that AuNPs and LPS augmented the production of cytosolic reactive oxygen species (ROS) in p38 and ERK dependent manner, through upregulating and activating NADPH oxidase 2 (NOX2). Accordingly, scavenging of ROS or inhibiting the NOX2 dampened NETs release induced by combined AuNPs and LPS treatment. AuNPs and LPS also synergized to upregulate reactive oxygen species modulator 1 (ROMO1) via activating ERK, thereby increasing mitochondrial ROS generation and promoting the release of NETs. In summary, we provide new evidences about the synergy of AuNPs and LPS to augment cellular responses in neutrophils, which implicates the need to consider the amplifying effect by pathogenic stimuli when utilizing nanomaterials in infectious or inflammatory conditions.
摘要：
金纳米粒子(AuNP)在生物医学领域被广泛使用。然而,它们与宿主细胞的潜在相互作用尚未得到全面阐明。在这项研究中,我们证明了AuNPs与细菌脂多糖(LPS)协同促进人外周血中性粒细胞释放中性粒细胞胞外陷阱(NETs)的大小依赖性效应.机械上,与40和100nmAuNP相比，LPS更有效地与10nmAuNP接触并促进其在嗜中性粒细胞中的摄取，导致A类清道夫受体（SRA）的协同上调，该受体介导AuNPs摄取并触发细胞外调节蛋白激酶（ERK）和p38的激活。阻断SRA或抑制ERK和p38激活显著消除了AuNP和LPS诱导NETs形成的作用。进一步的实验表明，AuNP和LPS以p38和ERK依赖性方式增加了细胞溶质活性氧（ROS）的产生。通过上调和激活NADPH氧化酶2（NOX2）。因此，清除ROS或抑制NOX2抑制AuNP和LPS联合治疗诱导的NETs释放。AuNP和LPS还通过激活ERK协同上调活性氧调节剂1（ROMO1），从而增加线粒体ROS的产生并促进NETs的释放。总之,我们提供了有关AuNPs和LPS协同增强中性粒细胞细胞反应的新证据，这意味着当在感染性或炎症条件下利用纳米材料时，需要考虑致病刺激的放大效应。
