SiO₂ and TiO₂ nanoparticles synergistically trigger macrophage inflammatory responses

Silicon dioxide (SiO₂) nanoparticles (NPs) and titanium dioxide (TiO₂) NPs are the most widely used inorganic nanomaterials. Although the individual toxicities of SiO₂ and TiO₂ NPs have been extensively studied, the combined toxicity of these NPs is much less understood. In this study, we observed unexpected and drastic activation of the caspase-1 inflammasome and production of IL-1β in mouse bone marrow-derived macrophages stimulated simultaneously with SiO₂ and TiO₂ NPs at concentrations at which these NPs individually do not cause macrophage activation. Consistent with this, marked lung inflammation was observed in mice treated intratracheally with both SiO₂ and TiO₂ NPs. In macrophages, SiO₂ NPs localized in lysosomes and TiO₂ NPs did not; while only TiO₂ NPs produced ROS, suggesting that these NPs induce distinct cellular damage leading to caspase-1 inflammasome activation. Intriguingly, dynamic light scattering measurements revealed that, although individual SiO₂ and TiO₂ NPs immediately aggregated to be micrometer size, the mixture of these NPs formed a stable and relatively monodisperse complex with a size of ~250 nm in the presence of divalent cations. Taken together, these results suggest that SiO₂ and TiO₂ NPs synergistically induce macrophage inflammatory responses and subsequent lung inflammation. Thus, we propose that it is important to assess the synergistic toxicity of various combinations of nanomaterials.