Club cell TRPV4 as a damage sensor driving lung allergic inflammation

Airway epithelium is the first body surface to contact inhaled irritants, yet the sensing of these inflammatory triggers is poorly understood. We studied how epithelial cells recognize and respond to protease, a critical component of many allergens that provoke asthma. In a murine model, the aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp. elicited helper T (Th) cell-dependent lung eosinophilia. Bronchiolar club cells responded rapidly to Alp1, coordinating the accumulation of allergic immune cells in the lung. Alp1 degraded bronchiolar cell junctions, with club cells propagating this signal via calcium and calcineurin to incite inflammation. In two human cohorts, we linked fungal sensitization and asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 was also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells sense junction damage as mechanical stress, which signals danger via TRPV4, calcium and calcineurin to initiate Th cell sensitization.