Nanoplastics dysregulate macrophage function by impairing glutathione metabolism

Micro- and nanoplastics (MNPs) are emerging environmental contaminants increasingly detected in human tissues. However, how MNP-related effector mechanisms that impact the immunological function of macrophages remain elusive. Here, we demonstrated that MNPs disrupt redox homeostasis and induce immune dysfunction in bone marrow-derived macrophages. MNP internalization in macrophages impairs mitochondrial function, inducing excessive and sustained production of reactive oxygen species along with suppressed glutathione metabolism, including the substantial down-regulation of key antioxidant enzymes, such as glutathione peroxidase (GPX) 1, GPX3, and GPX4. These processes cause oxidative imbalance, thereby triggering ferroptosis, compromising cellular integrity, and amplifying inflammatory signaling. Two-photon intravital and three-dimensional imaging in mice confirmed that orally administered MNPs accumulate in multiple organs. Such MNP accumulation exacerbates lung tumor progression, potentially through chronic inflammation and the immune dysregulation of macrophages. These findings reveal a novel mechanism by which MNPs alter innate immunity and promote an inflammatory microenvironment via redox-mediated ferroptosis. Total RNA-seq profiling of mouse bone marrow-derived macrophage and treated or no-treated by polystyrene micro- and nanoplastics.

微塑料与纳米塑料（Micro- and nanoplastics, MNPs）是一类新兴环境污染物，目前在人体组织中的检出率日益攀升。然而，MNPs影响巨噬细胞免疫功能的相关效应机制仍未明确。本研究证实，MNPs可破坏骨髓来源巨噬细胞的氧化还原稳态，并诱导其免疫功能失调。巨噬细胞对MNPs的内化作用会损伤线粒体功能，引发活性氧的过量且持续性生成，同时抑制谷胱甘肽代谢，包括谷胱甘肽过氧化物酶（glutathione peroxidase, GPX）1、GPX3与GPX4等关键抗氧化酶的显著下调。上述过程会引发氧化失衡，进而触发铁死亡、破坏细胞完整性，并放大炎症信号通路。小鼠体内的双光子活体成像与三维成像结果证实，经口摄入的MNPs可在多个脏器中蓄积。此类MNPs蓄积会加剧肺部肿瘤进展，其潜在机制可能与慢性炎症及巨噬细胞免疫失调相关。本研究揭示了MNPs通过氧化还原介导的铁死亡，改变先天免疫并促进炎症微环境形成的全新机制。本数据集包含经聚苯乙烯微/纳米塑料处理及未处理的小鼠骨髓来源巨噬细胞的总RNA测序（Total RNA-seq）谱数据。