Au nanorod-induced NLRP3 inflammasome activation is mediated by ER stress

Abstract

Abstract The widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to specific ENM properties by inflammatory reactions. Inflammasome activation has drawn significant attention since inflammasomes, especially NLRP3 respond to a wide range of stimuli including nanoparticles, and their activation is associated with various inflammatory diseases, including lung fibrosis, obesity and type-2 diabetes. Endoplasmic reticulum (ER) stress has been reported as one of the mechanisms underlying NLRP3 inflammasome activation. In this study, PEGylated Au ENM of ≈60 nm, having different shapes (stars, spheres and rods) were extensively characterized, and tested for possible LPS contamination. PMA-activated THP-1 cells were exposed to these ENM, and cell viability and IL-1β production were measured to assess NLRP3 activation. In addition, the exposed cells were subjected to gene expression analysis using microarray analysis to investigate related signalling pathway regulation. PEGylated Au nanorods (NR), but not nanostars or nanospheres, showed NLRP3 inflammasome activation. Cells deficient in the NLRP3 scaffold or ASC adaptor did not show this effect. Only NR-exposed cells showed down-regulation of ER-associated cholesterol metabolism. This finding may suggest that ER stress mediates NLRP3 inflammasome activation by Au NR. Supported by the EU funded project FutureNanoNeeds (Grant agreement N° 604602).