Dendritic cell activation by iron oxide nanoparticles depends on the extracellular environment

Nanoparticles can exert immune modulating effects in a host depending on composition, mode of administration, and type of disease. Although the specific mechanisms of nanoparticle-induced immune responses remain unclear, their uptake by macrophages and other phagocytic innate immune cells is considered to be a key event. Our objective here was to ascertain if nanoparticle-mediated activation of dendritic cells (DCs) occurs in vitro or in vivo when exposed to hydroxyethyl starch-coated iron oxide nanoparticles. For the present studies, our choice of nanoparticles, animal model, and experimental design is motivated by our previously published observations that systemic exposure can induce antitumor adaptive immune responses in mouse models of metastatic breast cancer. Here, we began by assessing the potential toxicity of systemic exposure to commercially available starch-coated Bionized Nanoferrite (R) nanoparticles (BP) by measuring body weight, complete blood count, and enzyme parameters in healthy FVB/NJ mice after repeated BP dosing. We observed no evidence of toxicity at doses up to 25 mg Fe per mouse, five-fold higher than those used in subsequent in vivo experiments. We then measured the expression of surface maturation markers (CD86, MHC II) in DCs incubated with BP in vitro. Although DCs cultured with BP revealed high levels of nanoparticle uptake, neither JAWSII dendritic cells nor bone marrow derived dendritic cells (BMDCs) showed significant changes in marker expression to indicate stimulation of maturation and effector function. To assess whether BP interactions in vivo produced different effects, we analyzed CD80, CD86, and MHC II expression of DCs recovered from the livers, spleens, bone marrows, and lymph nodes of mice injected once with BP (5 mg Fe). Interestingly, only DCs in spleens and bone marrow cells responded to BP exposure. DCs recovered from other organs showed no evidence of increased activation. These findings highlight complex interactions between living systems and nanoparticles, and their potential to mediate context-specific and selective activation of innate immune cells. Our study also emphasizes that results obtained from in vitro experiments must be interpreted with caution, as they may not faithfully represent responses in living systems.