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.
Bibliographical noteFunding Information:
We thank UW-Madison core facilities: Carbone Cancer Center ( NIH P30 CA014520 , 1S100OD018202-01 ), Biotechnology Center ( NIH P50 GM64598 , R33 DK070297 ; NSF DBI-0520825 , DBI-9977525 ) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J., J.E.G., R.A.B.-S., and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1 −/− mice.
- alkaline protease 1
- club cells