365 The MrgprB2/X2 is regulated by the neurokinin 2 receptor in mast cells in the skin

Abstract

In the cutaneous microenvironment, interactions between mast cells (MCs) and sensory neurons play an important role in immune responses. Neuropeptides such as neurokinin A and substance P direct MC function by initiating signaling through neurokinin (NKRs) receptors, and Mas related G-protein receptors (Mrgpr)s. Recent studies highlight the importance of the MrgprB2 (mouse) and MrgprX2 (human) in the MC response to pseudo-allergens, secretagogues and substance P. To date, a relationship between NKRs and the MrgprB2/X2 has not been investigated. In this study, we hypothesize that MrgprB2/X2 is transciptionally controlled by the NK2R and its high affinity ligand, neurokinin A. In mice, we show that administration of neurokinin A diminishes MrgprB2 RNA expression. Surprisingly, NK2R antagonism also downregulates MrgprB2 expression and MrgprB2 expression is markedly diminished in mice lacking the NK2R. In contrast, co-administration of neurokinin A and an NK2R antagonist increases MrgprB2 expression. The MC response to the canonical MrgprB2 ligand, compound 48/80, mirrored the changes in MrgprB2 transcript expression. In human skin explants, NK2R antagonism had minimal effect on MrgprX2 expression, but co-administration of neurokinin A and a NK2R antagonist markedly upregulated MrgprX2 expression, as seen in murine skin. These data demonstrate that the NK2R-signaling influences MrgprB2/X2 expression and, that in absence of the NK2R, neurokinin A interacts with an unknown receptor to increase MrpgrB2/X2 expression. Collectively, these data uncover a novel role for NK2R signaling in the regulation of MrgprB2/X2. These important findings have implications for patients with mast cell mediated cutanous inflammatory diseases.