Department Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Health Department, Flemish Institute for Technological Research, Mol, Belgium.
Arch Toxicol. 2020 Jan;94(1):173-186. doi: 10.1007/s00204-019-02604-5. Epub 2019 Nov 1.
Macrophages play a major role in the removal of foreign materials, including nano-sized materials, such as nanomedicines and other nanoparticles, which they accumulate very efficiently. Because of this, it is recognized that for a safe development of nanotechnologies and nanomedicine, it is essential to investigate potential effects induced by nano-sized materials on macrophages. To this aim, in this work, a recently established model of primary murine alveolar-like macrophages was used to investigate macrophage responses to two well-known nanoparticle models: 50 nm amino-modified polystyrene, known to induce cell death via lysosomal damage and apoptosis in different cell types, and 50 nm silica nanoparticles, which are generally considered non-toxic. Then, a time-resolved study was performed to characterize in detail the response of the macrophages following exposure to the two nanoparticles. As expected, exposure to the amino-modified polystyrene led to cell death, but surprisingly no lysosomal swelling or apoptosis were detected. On the contrary, a peculiar mitochondrial membrane hyperpolarization was observed, accompanied by endoplasmic reticulum stress (ER stress), increased cellular reactive oxygen species (ROS) and changes of metabolic activity, ultimately leading to cell death. Strong toxic responses were observed also after exposure to silica, which included mitochondrial ROS production, mitochondrial depolarization and cell death by apoptosis. Overall, these results showed that exposure to the two nanoparticles led to a very different series of intracellular events, suggesting that the macrophages responded differently to the two nanoparticle models. Similar time-resolved studies are required to characterize the response of macrophages to nanoparticles, as a key parameter in nanosafety assessment.
巨噬细胞在清除外来物质（包括纳米级材料，如纳米药物和其他纳米粒子）方面发挥着重要作用，它们非常有效地积累这些物质。正因为如此，人们认识到，为了安全地开发纳米技术和纳米医学，有必要研究纳米级材料对巨噬细胞可能产生的潜在影响。为此，在这项工作中，我们使用了最近建立的原代鼠肺泡样巨噬细胞模型来研究巨噬细胞对两种知名纳米颗粒模型的反应：50nm 氨基化聚苯乙烯，已知在不同细胞类型中通过溶酶体损伤和细胞凋亡诱导细胞死亡；50nm 二氧化硅纳米颗粒，通常被认为是无毒的。然后，我们进行了一项时间分辨研究，以详细描述巨噬细胞在暴露于这两种纳米颗粒后的反应。正如预期的那样，暴露于氨基化聚苯乙烯会导致细胞死亡，但令人惊讶的是，没有检测到溶酶体肿胀或细胞凋亡。相反，观察到一种特殊的线粒体膜超极化，伴随着内质网应激（ER 应激）、细胞内活性氧（ROS）增加和代谢活性的变化，最终导致细胞死亡。暴露于二氧化硅也会引起强烈的毒性反应，包括线粒体 ROS 产生、线粒体去极化和细胞凋亡导致的细胞死亡。总的来说，这些结果表明，暴露于这两种纳米颗粒会导致一系列非常不同的细胞内事件，表明巨噬细胞对这两种纳米颗粒模型的反应不同。为了在纳米安全评估中作为一个关键参数，需要对巨噬细胞对纳米颗粒的反应进行类似的时间分辨研究。
