Size-dependent superparamagnetic iron oxide nanoparticles dictate interleukin-1 release from mouse bone marrow-derived macrophages

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely investigated for their biomedical applications in magnetic resonance imaging, targeting therapy, cell labeling, etc. It has been well documented that macrophages produce interleukin (IL)-1 via several signaling pathways, such as inflammasome activation in response to particles including silica, asbestos and urea crystals with lipopolysaccharide priming. However, the size and dose effects of SPIONs on macrophages and the mechanisms remain unclear. In this study, we explored the cytotoxicity and mechanisms of the synthesized SPIONs with different size distributions of 30, 80 and 120nm, and compared their potential capability in inducing IL-1 release in mouse bone marrow-derived macrophages (BMMs). We found that SPIONs induced IL-1 release in a size- and dose-dependent manner, in which the smallest SPIONs triggered the highest IL-1 in BMMs. When cellular uptake of SPIONs was inhibited by the actin polymerization inhibitor, cytochalasin D, SPION-induced IL-1 release was suppressed in BMMs. Preventing lysosome damage with bafilomycin A1 or CA-074-Me also counteracted SPION-induced IL-1 release. Moreover, SPION-activated IL-1 release was also attenuated by reactive oxygen species scavengers, diphenylene iodonium or N-acetylcysteine. Our results elucidated the effects of size and dose on the cytotoxicity and mechanisms of IL-1 release of SPIONs on macrophages, which facilitate the theoretical and experimental application of SPIONs in biotechnology and biomedicine in the future. Superparamagnetic iron oxide nanoparticles (SPIONs) are widely applied in the biomedical field. However, SPIONs' size and dose effects on macrophages and their mechanisms remain unclear. We showed that SPIONs induced interleukin-1 release in bone marrow-derived macrophages in a size- and dose-dependent manner. Inhibiting cellular uptake, preventing lysosome damage or scavenging reactive oxygen species could suppress SPION-induced interleukin-1 release. Our study provides the scientific basis for screening appropriate SPION sizes and facilitates the theoretical and experimental application of SPIONs in biotechnology and biomedicine in the future.