Iron oxide nanoparticles size-dependently activate mouse primary macrophages via oxidative stress and endoplasmic reticulum stress

Iron oxide nanoparticles (IONPs) are widely used in cosmetics, food additives, and biomedical fields. There are a few adverse effects of IONPs according to clinical reports and animal studies. However, the immunotoxicity and, in particular, the size effects and mechanisms of IONPs on macrophages have not been fully clarified. This study aimed to explore the impacts of 10 nm and 30 nm IONPs on immune responses both in mice and bone marrow-derived macrophages (BMMs). We found that 10 mg/kg IONPs elevated the number of neutrophils and the level of interleukin-6 (IL-6) in peritoneal lavage fluids in mice. IONPs also provoked BMMs and induced the production of IL-6 and tumor necrosis factor-α (TNF-α). The impacts of IONPs on inflammatory responses were size-dependent, and 30 nm IONPs were stronger. Consistently, RNA-sequencing and bioinformatic analysis showed that 30 nm IONPs activated numerous biological processes, including many immune responses, endoplasmic reticulum (ER) stress, and oxidative stress. Furthermore, the inflammatory response caused by IONPs could be attenuated by blocking actin polymerization, ER stress, or oxidative stress. This study is helpful to understand the biosafety of IONPs and protect humans from their potential adverse immune effects.