258 - The transient receptor potential vanilloid 1 (TRPV1) channel is a critical factor in allergen-induced innate immune responses in the airway epithelium

Abstract

The airway epithelium plays a critical role in innate responses to asthma-relevant protease allergens, such as house dust mite (HDM) or Alternaria alternata (ALT), by rapid secretion of IL-1 family alarmins, such as interleukin (IL)-1α and IL-33, that orchestrate appropriate type 2 immune responses. Previous studies indicate that allergen-induced IL-33 secretion is mediated by protease-activated receptors (PAR2) and type 2 purinergic receptors (P2RY2), which induce Ca2+-dependent signaling and activation of the NADPH oxidase dual oxidase 1 (DUOX1). Transient receptor potential (TRP) Ca2+ channels such as TRP Vanilloid 1 (TRPV1) are important in e.g. pain responses, often in coordination with PAR2 and P2YR2 activation, and TRPV1 has recently been implicated in asthma pathology. Using a panel of pharmacological inhibitors and activators of P2YR2, PAR2, and TRPV1, we observed that each of these receptors can provoke activation of DUOX1 and secretion of IL-33 in primary human nasal epithelial (HNE) cells. Further mechanistic studies using primary mouse tracheal epithelial cells (MTECs) or human bronchial epithelial cells (HBE1) confirmed these findings, and showed that TRPV1 contributes importantly to innate responses to HDM and ALT, and the danger signal ATP which activates P2YR2, as shown by activation of DUOX1-dependent H2O2 production, activation of epidermal growth factor receptor signaling, and rapid secretion of IL-33, which were prevented using TRPV1 antagonists or TRPV1-siRNA. Strikingly, inhibition or siRNA silencing of P2YR2 also prevented innate responses to the TRPV1 activator capsaicin, highlighting a close functional relationship of these airway epithelial surface receptors in the innate allergen responses. Finally, airway IL-33 secretion and subsequent type 2 cytokine production in mice in response to acute airway HDM challenge were markedly impaired in TRPV1-deficient mice. Overall, our studies indicate a complex relationship between various receptor types in epithelial responses to environmental triggers, and highlight the importance of TRPV1 in such epithelial responses.