Signaling via neurokinin 1 and 2 receptors exerts opposing effects on mast cell pro-inflammatory and Th2-biasing functions. (HYP3P.347)

Abstract

Abstract Following activation via FcεRI, peripheral tissue mast cells (MCs) initiate and sustain atopic diseases, by secreting proinflammatory and Th2 biasing cytokines. MC express neuropeptide receptors and are exposed to neuroinflammatory mediators. However, the role of neuropeptides in FcεRI-activated MCs remains mainly unknown. Two of the most potent pro-inflammatory neuropeptides, substance-P (SP) and hemokinin-1 (HK-1), bind with high affinity to the neurokinin 1 receptor (NK1R) and with lower affinity to the NK2R. We addressed in vitro and in vivo the role of the NK1R and NK2R in MC responses initiated via FcεRI. In vitro, FcεRI activation of bone marrow derived (BM)MCs from wild type (WT) mice increased NK1R and NK2R expression and HK-1 release, but not release of SP. Utilizing NK1R-/- BMMCs, we determined that the NK1R was necessary for Akt-NFκB signaling and for the secretion of the pro-inflammatory TNF-α, IL-6 and Th2 biasing IL-4 and IL-13. Conversely, inhibition of NK2R signaling in WT BMMCs with GR159897 decreased the release of proinflammatory and Th2 cytokines. In vivo, NK1R signaling was necessary for amplifying IgE-Ag mediated cutaneous and systemic anaphylaxis and chronic asthma. We conclude that NK1R and the NK2R display opposing effects on the inflammatory function of FcεRI-activated MCs relevant for the control of MC derived atopic disorders.