Abstract
The application of nanotechnology in the health care setting has many potential benefits; however, our understanding of the interactions between nanoparticles and our immune system remains incomplete. Although many of the biological effects of nanoparticles are negatively correlated with particle size, some are clearly size specific and the mechanisms underlying these size-specific biological effects remain unknown. Here, we examined the pro-inflammatory effects of silica particles in THP-1 cells with respect to particle size; a large overall size range with narrow intervals between particle diameters (particle diameter: 10, 30, 50, 70, 100, 300, and 1,000 nm) was used. Secretion of the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α induced by exposure to the silica particles had a bell-shaped distribution, where the maximal secretion was induced by silica nanoparticles with a diameter of 50 nm and particles with smaller or larger diameters had progressively less effect. We found that blockade of IL-1β secretion markedly inhibited TNF-α secretion, suggesting that IL-1β is upstream of TNF-α in the inflammatory cascade induced by exposure to silica particles, and that the induction of IL-1β secretion was dependent on both the NLRP3 inflammasome and on uptake of the silica particles into the cells via endocytosis. However, a quantitative analysis of silica particle uptake showed that IL-1β secretion was not correlated with the amount of silica particles taken up by the cells. Further investigation revealed that the induction of IL-1β secretion and uptake of silica nanoparticles with diameters of 50 or 100 nm, but not of 10 or 1,000 nm, was dependent on scavenger receptor (SR) A1. In addition, of the silica particles examined, only those with a diameter of 50 nm induced strong IL-1β secretion via activation of Mer receptor tyrosine kinase, a signal mediator of SR A1. Together, our results suggest that the SR A1-mediated pro-inflammatory response is dependent on ligand size and that both SR A1-mediated endocytosis and receptor-mediated signaling are required to produce the maximal pro-inflammatory response to exposure to silica particles.
Highlights
The application of nanotechnology is a promising means of developing novel diagnostic and imaging technologies, photothermal therapies, vaccines, and drug delivery systems [1,2,3]
The present results suggest that scavenger receptor (SR)-A1-mediated endocytosis underlies silica particle-induced IL-1β secretion, and that the sizespecific pro-inflammatory effects of silica particles are a result of the ligand size specificity of this SR-A1-mediated endocytosis
The present results suggest that silica particles with a diameter of 50 nm induced the strongest pro-inflammatory response
Summary
The application of nanotechnology is a promising means of developing novel diagnostic and imaging technologies, photothermal therapies, vaccines, and drug delivery systems [1,2,3]. There are two main factors that make nanoparticles more effective and more hazardous than the bulk material The first is their ability to cross biological barriers [e.g., blood– brain barrier [8], placental barrier [9], blood–milk barrier [10], and nuclear barrier [11]]. It has been reported that in a comparison of nanoparticle-based antitumor vaccines that differed only with respect to particle diameter (20, 40, 100, 200, 500, 1,000, or 2,000 nm), the vaccine with a particle diameter of 40 nm was the most effective [22] Together, these studies demonstrate that size-specific biological effects of nanoparticles exist and that particles with diameters of around 50 nm induce the strongest biological effects. Further studies are needed to elucidate the mechanisms underlying these size-specific effects
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