Pseudomonas aeruginosa-derived volatile organic compounds modulate AhR signaling to dysregulate airway mucus homeostasis

Pseudomonas aeruginosa frequently infects chronically diseased lungs and exacerbates airway mucus hypersecretion and failure in clearance. P. aeruginosa is metabolically versatile and secretes multiple volatile organic compounds (VOCs), which have been scrutinized as potential biomarkers for diagnosing acute exacerbation in diseased lungs. However, the pathogenic roles of VOCs in mucus dysregulation are unknown. By using air-liquid interface cultures of normal and diseased human bronchial epithelial cells and a mouse model of chronic VOCs exposure, we report that dominant species of P. aeruginosa VOCs in concentrations found in both the breath of cystic fibrosis patients and in the headspace of bacterial cultures significantly elevated the expression of the mucin MUC5AC. VOCs activate the AhR signaling to inhibit FOXA2, a key regulator of airway mucus homeostasis. AhR inhibitor restored FOXA2 expression to attenuate excessive mucin expression. Mechanistic studies revealed that P. aeruginosa VOCs activate the AhR-ARNT-CYP1-ROS signaling cascade, which in turn induces the EGFR-AKT/ERK signaling pathways to disrupt airway mucus homeostasis. Taken together, these findings highlight the critical role of P. aeruginosa VOCs in disrupting airway mucus homeostasis and implicate the pathogenic role of AhR signaling in chronic lung diseases.