Silica nanoparticles activate purinergic signaling via P2X7 receptor in dendritic cells, leading to production of pro-inflammatory cytokines

We examined the mechanism of SNP-mediated stimulation of IL-1 beta and IL-18 production via P2R-mediated pathways in mouse bone marrow dendritic cells (mBMDCs). Examination of uptake of SNPs with diameters of 30, 70, and 300 nm (SNP30, SNP70, and SNP300, respectively) by lipopolysaccharide-matured mBMDCs revealed that significant uptake of SNP30 occurred within as short a time as 1 h. Production of IL-1 beta and IL-18 by cells exposed to SNPs increased dose-dependently, and was highest in cells exposed to SNP30. The SNP30-induced cytokine production was significantly inhibited by ATPase (apyrase) and by P2X(7) receptor antagonist (A438079). ATP release was also highest in SNP30-exposed cells. Treatment of mBMDCs with exogenous ATP induced release of high levels of IL-1 beta and IL-18, and this release was also significantly inhibited by apyrase and A438079. The order of effectiveness of the three SNPs for inducing intracellular reactive oxygen species (ROS) production accorded well with those of cytokine production and ATP release. ROS production was inhibited by diphenyleneiodonium chloride (DPI). SNPs, especially SNP30, activate purinergic signaling in matured mBMDCs by inducing ATP release via P2X(7) receptor. ATP induces ROS production via NADPH oxidase, and ROS activate infiammasomes, leading to caspase-1-dependent processing of pro-cytoldnes and release of IL-1 beta. and IL-18. (C) 2016 Elsevier Ltd. All rights reserved.