SiO2 oral exposure promotes the crosstalk between NETs and PANoptosis of lung epithelial cells by driving NOX1/ROS, triggering pneumonia in mice.

With the continuous increase in production and application, the environmental pollution caused by SiO2 nanoparticles and their potential harm to human and animal health cannot be ignored. Under pathological conditions, the formation of extracellular traps in inflammatory cells as well associated-inflammatory responses partially attribute to nicotinamide adenine dinucleotide phosphate oxidase (NOX)-mediated oxidative burst. However, it remains unclear whether NOX/reactive oxygen species (ROS) promote the formation of neutrophil extracellular traps (NETs) to mediate the induction of pneumonia in mice by SiO2. In this study, we exposed C57/6 J mice to SiO2 of different particle sizes via intragastric administration. Results showed that SiO2 exposure evoked neutrophil infiltration in lung tissue in a particle size-dependent manner. Transcriptomic analysis revealed that SiO2 exposure activated NOX1/ROS, which, on the one hand, drove NETs production, and on the other hand, triggered PANoptosis in lung epithelial cells, promoting the release of damage associated molecular patterns (DAMPs), pro-inflammatory cytokines, and chemokines. Co-cultivation experiments indicated that the enhanced chemotaxis signals in epithelial cells further accelerated NETs release, which in turn exacerbated epithelial cells death, contributing to a vicious cycle of inflammation. Thus, our study uncovered the mechanism, that NOX1-mediated oxidative stress as a hub, enhancing the crosstalk between lung epithelial cells PANoptosis and neutrophils NETs formation, exacerbating pneumonia in mice, under conditions of SiO2 exposure. Our research enriched the toxicological mechanism of SiO2 and provided reference for comparative medicine.