Amino‐functionalized polystyrene nanoparticles activate the NLRP3 inflammasome in human macrophages

Abstract

Nanoparticles are increasingly used in different biological and biomedical applications. However, their impact on cell functions is not well understood. Here we demonstrate that aminofunctionalized polystyrene nanoparticles (PS‐NH2) of ~100 nm but not carboxy‐functionalized (PS‐COOH) or non‐functionalized (PS) particles of the same size induce NLRP3 inflammasome activation and subsequent release of IL‐1β by human macrophages. PS‐NH2 were found to induce time‐dependent lysosomal destabilization followed by release of lysosomal enzymes, which trigger mitochondrial damage and increased formation of reactive oxygen species (ROS). Accumulation of mitochondria‐derived ROS causes oxidation of thioredoxin and its dissociation from the thioredoxin‐interacting protein (TXNIP). Liberated TXNIP forms a complex with the inflammasome, which promotes recruitment and activation of caspase‐1 followed by processing of pro‐IL‐1β to IL‐ 1β. Treatment of macrophages with the ROS scavenger N‐acetyl‐ L‐cysteine abolishes both, the caspase‐1 activation and the subsequent release of IL‐1β. Using an in vitro knockdown approach, we showed that PS‐NH2 but not PS‐COOH or PS induce activation of specifically the NLRP3 inflammasome. Thus, aminofunctionalized nanoparticles may induce proinflammatory activation of human macrophages, an effect that can be antagonized by radical scavengers. Supported by the DFG.