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Previous studies revealed that epithelial IL-33 secretion by allergens such as Alternaria alternata or house dust mite involves Ca2+-dependent signaling, via initial activation of ATP-stimulated P2YR2 (type 2 purinoceptor) and subsequent activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase DUOX1. We sought to identify proximal mechanisms by which epithelial cells sense these allergens and here highlight the importance of PAR2 (protease-activated receptor 2) and TRP (transient receptor potential) Ca2+ channels such as TRPV1 (TRP vanilloid 1) in these responses. Combined studies of primary human nasal and mouse tracheal epithelial cells, as well as immortalized human bronchial epithelial cells, indicated the importance of both PAR2 and TRPV1 in IL-33 secretion by both Alternaria alternata and house dust mite, based on both pharmacological and genetic approaches. TRPV1 was also critically involved in allergen-induced ATP release, activation of DUOX1, and redox-dependent activation of EGFR (epidermal growth factor receptor). Moreover, genetic deletion of TRPV1 dramatically attenuated allergen-induced IL-33 secretion and subsequent type 2 responses in mice in vivo. TRPV1 not only contributed to ATP release and P2YR2 signaling but also was critical in downstream innate responses to ATP, indicating potentiating effects of P2YR2 on TRPV1 activation. In aggregate, our studies illustrate a complex relationship between various receptor types, including PAR2 and P2YR2, in epithelial responses to asthma-relevant airborne allergens and highlight the central importance of TRPV1 in such responses.<\/jats:p>","DOI":"10.1165\/rcmb.2019-0170oc","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T15:17:22Z","timestamp":1584458242000},"page":"198-208","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":44,"title":["The Transient Receptor Potential Channel Vanilloid 1 is Critical in Innate Airway Epithelial Responses to Protease Allergens"],"prefix":"10.1093","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-1168","authenticated-orcid":false,"given":"Caspar","family":"Schiffers","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont; and"},{"name":"Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Hristova","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Habibovic","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8372-3719","authenticated-orcid":false,"given":"Christopher M.","family":"Dustin","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karamatullah","family":"Danyal","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niki L.","family":"Reynaert","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiel F. 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