Signaling via neurokinin-1 receptor stimulates mast cell pro-inflammatory and Th2 biasing functions (P6008)

Abstract

Abstract Pro-inflammatory mast cells (MC) are crucial for initiation and perpetuation of anaphylaxis and atopic diseases. TNFα secretion by activated MC is critical for MC-mediated inflammation. Efficient MC activation depends on exogenous stimuli triggering endogenous mediators, such as pro-inflammatory neuropeptides. Surprisingly, studies linking neuromediators to MC are lacking. Here we analyzed the role of the neuropeptides, substance-P (SP) and hemokinin-1 (HK-1), in the regulation of IgE-mediated MC inflammation. In vitro, we show that MC express the shared receptor for SP and HK-1, the neurokinin-1 receptor (NK1R). FcϵRI ligation of bone marrow derived MC (BMMC) from WT mice increased HK-1 and NK1R mRNA and protein levels but had no effect on SP. NK1R-/- BMMC had significantly decreased degranulation and TNFα release suggesting that autocrine HK-1 promoted MC inflammatory functions. Mechanistic analysis demonstrated that NK1R-/- BMMC had impaired Akt-dependent NFκB activation. In vivo, NK1R-/- mice showed significantly decreased IgE-mediated cutaneous and systemic anaphylaxis and reduced development of chronic asthma, marked by reduced pulmonary eosinophilia, reduced Th2 skewing and low levels of TNFα in bronchial fluid. We conclude that MC utilize a positive feedback loop whereby autocrine HK-1 induces NK1R signaling that, in turn, potentiates TNFα secretion in the course of IgE-mediated anaphylactic and atopic disorders.