Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation
Résumé
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.
Mots clés
Allergens
Animals
Aspergillus fumigatus
Asthma
Bronchioles
Calcineurin
Calcium Channels
Calcium Signaling
Cohort Studies
Eosinophilia
Epithelial Cells
Humans
Inflammation
Mice
Mice, Inbred C57BL
Serine Endopeptidases
T-Lymphocytes
TRPV Cation Channels
Aspergillus
TRPV4
alkaline protease 1
asthma
calcineurin
calcium
club cells