Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice

BACKGROUND: Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. METHODS: Wild-type (WT), Notch3 (Notch3(–/–)), and Notch4 (Notch4(–/–)) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6–72 hr. RESULTS: Relative to air-exposed controls, ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4(–/–) compared with WT and Notch3(–/–) mice. Significantly greater mean numbers of BALF neutrophils were found in Notch3(–/–) and Notch4(–/–) mice compared with WT mice after ozone exposure. Expression of whole lung Tnf was significantly increased after ozone in Notch3(–/–) and Notch4(–/–) mice, and was significantly greater in Notch3(–/–) compared with WT mice. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. CONCLUSIONS: These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation. CITATION: Verhein KC, McCaw Z, Gladwell W, Trivedi S, Bushel PR, Kleeberger SR. 2015. Novel roles for Notch3 and Notch4 receptors in gene expression and susceptibility to ozone-induced lung inflammation in mice. Environ Health Perspect 123:799–805; http://dx.doi.org/10.1289/ehp.1408852