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. Overall design: 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持续升高。然而，MNPs影响巨噬细胞免疫功能的相关效应机制仍不明晰。本研究证实，MNPs会破坏骨髓来源巨噬细胞的氧化还原稳态并诱导免疫功能失调。巨噬细胞对MNPs的内化作用会损伤线粒体功能，引发过量且持续的活性氧生成，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。上述过程会导致氧化失衡，进而诱发铁死亡、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实验证实，经口摄入的MNPs会在多个器官中蓄积。此类MNPs蓄积可通过慢性炎症与巨噬细胞免疫失调，加剧肺部肿瘤进展。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、促进炎症微环境的全新机制。整体实验设计：对经聚苯乙烯微塑料与纳米塑料处理及未处理的小鼠骨髓来源巨噬细胞开展总RNA测序转录组分析。