Aryl hydrocarbon receptor (AHR)-dependent protection against lung vascular leakage in viral infection

Disruption of the lung endothelial-epithelial cell barrier during respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function. Endothelial cell dysfunction is known to exacerbate tissue damage; however, it is unclear whether the lung endothelium engages in tissue-protective activity during viral infection. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is predominantly active in endothelial cells and protects against influenza-induced lung damage. Endothelial-specific AHR deletion caused increased vascular leakage in air spaces and enhanced influenza-induced lung tissue pathology. Global expression profiling revealed limited AHR-dependent regulation of vessels in the steady-state lung. However, following influenza-induced tissue damage and inflammation, AHR engages tissue-protective programmes in endothelia and prevents a dysplastic keratinised and apoptotic signature in the airways of infected lungs. Wild-type (wt) mice or mice with taregetd disruption of the AHR locus in endothelial cells were infected with influenza virus or treated with vehicle (PBS), and lung epithelial or endothelial cells were prepared on day 6 of infection for transcriptomic analysis.