Effect of Silica Particle Size on Macrophage Inflammatory Responses

Abstract

Amorphous silica particles, such as nanoparticles (<100 nm diameter particles), are used in a wide variety of products, including pharmaceuticals, paints, cosmetics, and food. Nevertheless, the immunotoxicity of these particles and the relationship between silica particle size and pro-inflammatory activity are not fully understood. In this study, we addressed the relationship between the size of amorphous silica (particle dose, diameter, number, and surface area) and the inflammatory activity (macrophage phagocytosis, inflammasome activation, IL-1β secretion, cell death and lung inflammation). Irrespective of diameter size, silica particles were efficiently internalized by mouse bone marrow-derived macrophages via an actin cytoskeleton-dependent pathway, and induced caspase-1, but not caspase-11, activation. Of note, 30 nm-1000 nm diameter silica particles induced lysosomal destabilization, cell death, and IL-1β secretion at markedly higher levels than did 3000 nm-10000 nm silica particles. Consistent with in vitro results, intra-tracheal administration of 30 nm silica particles into mice caused more severe lung inflammation than that of 3000 nm silica particles, as assessed by measurement of pro-inflammatory cytokines and neutrophil infiltration in bronchoalveolar lavage fluid of mice, and by the micro-computed tomography analysis. Taken together, these results suggest that silica particle size impacts immune responses, with submicron amorphous silica particles inducing higher inflammatory responses than silica particles over 1000 nm in size, which is ascribed not only to their ability to induce caspase-1 activation but also to their cytotoxicity.

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

“…58 SiNPs accumulation in lysosomes has been suggested as a mechanism of cytotoxicity in lung epithelial cells, and its overload leading to delayed clearance and particle persistence can negatively impact lysosome function. 59 It has been reported that internalized SiNPs could cause destabilization of lysosomes and permeabilization of lysosome membranes, 60 resulting in ROS generation, cytosolic acidification, and eventually cellular death. 61,62 Additionally, lysosome is vulnerable to ROS generated by NPs.…”

Effect of silica and gold nanoparticles on macrophage proliferation, activation markers, cytokine production, and phagocytosis in vitro

“…36 In their study, they noted that the smaller NPs (30-1,000 nm) induced a greater inflammatory response than the larger NPs. Our study also shows a similar result, with only the 10 nm silica NP showing any difference in cytokine production.…”

In vivo toxicologic study of larger silica nanoparticles in mice

“…22 Inflammatory responses presenting as elevated interleukin-1β were elicited more by smaller particles when different size, dose, concentration, and surface area mixtures of SiNPs were internalized by mouse bone marrow-derived macrophages. 23 Sohaebuddin et al 24 reported that SiO 2 nanoparticles of 30 nm diameter induced apoptosis of the cocultured cells with increasing percentages in 3T3 fibroblasts, human bronchiolar epithelial cells, and RAW macrophages, reaching ~10%, 50%, and 90%, respectively; however, little necrosis was observed in these studied cells. In contrast, limited cytotoxicity, measured as global metabolism activity, was seen when human epithelial intestinal HT-29 cells were exposed to both 25 and 100 nm nano-SiO 2 particles for 24 hours.…”

“…Pulmonary inflammation was detected by microcomputed tomography in mice lungs after intratracheal injection with the SiNPs of 30 or 3,000 nm, and smaller particles caused more severe complications. 23 Many studies demonstrated that most porous SiNPs deposited in liver and spleen when administered via blood and most of them were cleared in ,1 month. 28,29 Delayed clearance was noted when nonporous amorphous SiNPs were given intravenously to mice, and elevated aminotransferases, increased inflammatory cytokines, and hepatocytic necrosis were also found.…”