Abstract

Bystander effects in biological systems are the responses shown by nontargeted neighboring cells, and critical to the bio-nano interface interactions. In addition to direct effects, bystander effects also determine the design, applications and safety of nanomaterials, although the related information of nanomaterial-induced bystander effects remain largely unknown. A coculture system of A549 and THP-1 was established to mimic the lung microenvironment to study the bystander effects of WS₂ nanosheets (representative transition-metal dichalcogenide nanosheets) on microenvironment macrophages during the inhalation exposure or the nanomaterial biomedical application in the lung. Lung cells exposed to WS₂ nanosheet resulted in an increase in reactive oxygen species and the depolarization of mitochondrial membrane potential in neighboring macrophages. Bystander exposure also induced macrophage polarization toward the anti-inflammatory M2 phenotype, which is adverse to disease therapy. Metabolomics showed that WS₂ nanosheets disturbed the energy metabolism and amino acid metabolism of macrophages, consistent with the metabolic characteristics of M2 macrophages. Nitric oxide-transforming growth factor-β1 played an important mediator in the bystander effects. Importantly, WS₂ nanosheet bystander exposure affected macrophage phagocytosis and migration and altered the macrophage immune response to endotoxin. This study improves the current understanding of bio-nano interactions and highlights the importance of neighboring cell responses, allowing us to use the maximum benefits of nanomaterials while limiting their adverse bystander effects.

摘要

生物系统中的旁观者效应是非靶向邻近细胞显示的反应，对生物-纳米界面相互作用至关重要。除了直接效应，旁观者效应还决定了纳米材料的设计，应用和安全性，尽管有关纳米材料诱发的旁观者效应的相关信息仍然未知。建立A549和THP-1的共培养系统来模拟肺微环境，以研究WS ₂纳米片（代表性的过渡金属二硫化二氢纳米片）对吸入环境或纳米材料在肺中的生物医学应用对微环境巨噬细胞的旁观者效应。暴露于WS _2的肺细胞纳米片导致活性氧种类的增加和邻近巨噬细胞线粒体膜电位的去极化。旁观者暴露也引起巨噬细胞向抗炎M2表型极化，这不利于疾病治疗。代谢组学研究表明，WS ₂纳米片干扰了巨噬细胞的能量代谢和氨基酸代谢，与M2巨噬细胞的代谢特征一致。一氧化氮转化生长因子-β1在旁观者效应中起重要中介作用。重要的是，WS ₂纳米片旁观者暴露影响巨噬细胞的吞噬作用和迁移，并改变了巨噬细胞对内毒素的免疫反应。这项研究提高了当前对生物-纳米相互作用的理解，并强调了邻近细胞反应的重要性，使我们能够利用纳米材料的最大益处，同时限制其不利的旁观者效应。