Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses

Background: Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after Fc epsilon RI cross-linking by antigen-IgE complexes (Fc epsilon RI-activated mast cells [Fc epsilon RI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in Fc epsilon RI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking. Objective: We sought to investigate the effect of NK1R signaling and the individual roles of SP and HK-1 as potential adjuvants for Fc epsilon RI-MC-mediated allergic disorders. Methods: Bone marrow-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on Fc epsilon RI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on Fc epsilon RI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation. Results: Fc epsilon RI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor kappa B pathways. In vivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation. Conclusions: Fc epsilon RI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of Fc epsilon RI-MC-mediated disorders.