Pseudomonas aeruginosa-derived volatile organic compounds modulate host immunity to disrupt airway mucus homeostasis.

Chronic pulmonary diseases, including cystic fibrosis, chronic obstructive pulmonary disease, and chronic bronchitis, as well as ventilator-associated pneumonia, are characterized by persistent infection of mucus-laden airways. Pseudomonas aeruginosa (PA) is a dominant pathogen in these conditions and produces volatile organic compounds (VOCs) that have been proposed as biomarkers of disease exacerbation; however, their immunopathogenic roles remain unclear. We investigated PA-derived VOCs using human bronchial epithelial air-liquid interface cultures and murine models. VOCs exposure significantly increased airway mucin expression and induced a proinflammatory response characterized by M1 macrophage polarization (iNOS+), neutrophil recruitment, and expansion of IL-17A-producing Thy1.2+ lymphocytes. Functional depletion of macrophages, neutrophils, or IL-17A in vivo each attenuated mucin production and goblet cell metaplasia, indicating non-redundant contributions to mucus pathology. In vitro, IL-17A neutralization partially restored FOXA2 expression and reduced mucin production, supporting a role in mucus regulation. On the mechanistic level, we discovered an IL-17A-dependent dual-axis pathway involving both epithelial cell-mediated autocrine and lymphocyte-mediated paracrine signaling that contributes to the feed-forward loop of inflammation and enhances the signaling pathways regulating mucus hypersecretion in airways. We conclude that PA VOCs activate multiple proinflammatory responses to convergently drive mucus pathogenesis in the diseased lung.