Towards predictive nanotoxicology: from roundabout of molecular events to chronic inflammation prediction

Many chronic diseases manifest themselves in prolonged inflammation and often ignored dysregulated lipid metabolism, both also associated with inhalation of certain nanomaterials. Limited knowledge of involved molecular events and their causal connections prevents reliable prediction of outcomes by efficient testing strategies. To unravel how acute nanomaterial exposure leads to chronic conditions, we employed advanced microscopy and omics in vitro, in vivo and in silico. For selected metal-oxide nanomaterials, we show that epithelial cells survive the exposure by excreting internalized nanomaterials and passivating them on the surface, employing elevated lipid synthesis. Macrophages, on the contrary, attack the defending epithelium but die degrading passivized complexes, releasing nanomaterial, which is reuptaken by epithelial cells. Constant proinflammatory signalling recruits new phagocytes that feed the vicious cycle of events resulting in a long-lasting response to a single exposure. The discovered mechanism predicts the nanomaterial-associated in vivo chronic outcomes based on simple in vitro measurements and potentially enlightens other chronic diseases.