Up-regulation of miR-297 mediates aluminum oxide nanoparticle-induced lung inflammation through activation of Notch pathway

Abstract

Exposure to Aluminum oxide nanoparticles (Al₂O₃ NPs) has been associated with pulmonary inflammation in recent years; however, the underlying mechanism that causes adverse effects remains unclear. In the present study, we characterized microRNA (miRNA) expression profiling in human bronchial epithelial (HBE) cells exposed to Al₂O₃ NPs by miRNA microarray. Among the differentially expressed miRNAs, miR-297, a homologous miRNA in Homo sapiens and Mus musculus, was significantly up-regulated following exposure to Al₂O₃ NPs, compared with that in control. On combined bioinformatic analysis, proteomics analysis, and mRNA microarray, NF-κB-activating protein (NKAP) was found to be a target gene of miR-297 and it was significantly down-regulated in Al₂O₃ NPs-exposed HBE cells and murine lungs, compared with that in control. Meanwhile, inflammatory cytokines, including IL-1β and TNF-α, were significantly increased in bronchoalveolar lavage fluid (BALF) from mice exposed to Al₂O₃ NPs. Then we set up a mouse model with intranasal instillation of antagomiR-297 to further confirm that inhibition of miR-297 expression can rescue pulmonary inflammation via Notch pathway suppression. Collectively, our findings suggested that up-regulation of miR-297 expression was an upstream driver of Notch pathway activation, which might be the underlying mechanism involved in lung inflammation induced by exposure to Al₂O₃ NPs.

Keywords: Aluminum oxide nanoparticle; Lung inflammation; Nanotoxicology; Notch; microRNA.