The airway epithelium plays a critical role in innate responses to airborne allergens by secreting IL-1 family cytokines such as interleukin (IL)-1α and IL-33, as alarmins that subsequently orchestrate appropriate immune responses. Previous studies revealed that epithelial IL-33 secretion by allergens such as A. alternaria (ALT) or house dust mite (HDM) involves Ca2+-dependent signaling, via initial activation of ATP-stimulated type 2 purinoceptors (P2YR2) and subsequent activation of the NADPH oxidase DUOX1. We sought to identify proximal mechanisms by which epithelial cells sense these allergens, and here highlight the importance of protease-activated receptors (PAR2) and transient receptor potential (TRP) Ca2+ channels such as TRP Vanilloid 1 (TRPV1) in these responses. Combined studies of primary human nasal and mouse tracheal epithelial cells, as well as immortalized human bronchial epithelial cells (HBE1), indicated the importance of both PAR2 and TRPV1 in IL-33 secretion by both ALT and HDM, 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. 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 was also 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.
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