Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation.

Airway epithelium is the first body surface to contact inhaled irritants and report danger. Here, we report how epithelial cells recognize and respond to aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp., because proteases are critical components of many allergens that provoke asthma. In a murine model, Alp1 elicits helper T (Th) cell-dependent lung eosinophilia that is initiated by the rapid response of bronchiolar club cells to Alp1. Alp1 damages bronchiolar cell junctions, which triggers a calcium flux signaled through calcineurin within club cells of the bronchioles, inciting inflammation. In two human cohorts, we link fungal sensitization and/or asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 is also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells detect junction damage as mechanical stress, which signals danger via TRPV4, calcium, and calcineurin to initiate allergic sensitization. • An inhaled fungal protease allergen damages the junctions of bronchiolar club cells • The mechanosensor TRPV4 senses the junction injury, triggering allergic inflammation • TRPV4 is sufficient for inflammation in mice and linked with fungal asthma in humans • Calcineurin mediates TRPV4-dependent calcium signaling within bronchiolar club cells Wiesner et al. show a secreted fungal protease allergen of humans induces inflammation in mice with hallmarks of allergic asthma. The protease damages junctions of bronchiolar epithelial club cells, which the mechanosensor and gated calcium channel TRPV4 detects. Calcineurin mediates the calcium signaling and cellular alarms initiating lung allergic inflammation. [ABSTRACT FROM AUTHOR]