The pseudo-allergy receptor, MrgprB2/X2 is controlled by neurokinin A and the neurokinin 2 receptor in human and mouse skin

Within the skin, mast cells (MCs) and sensory neurons form a cohesive unit that plays an important role in initiating immune responses. Neuropeptides such as neurokinin A and substance P direct MC function by initiating signaling through neurokinin (NK) receptors, and Mas related G-protein receptors (Mrgpr)s. Neurokinin A, in particular, is thought to signal through the NK2R. 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 neurokinin receptors and the MrgprB2/X2 has not been investigated. In this study, we hypothesize that MrgprB2/X2 expression is controlled by the NK2R and its high affinity ligand, neurokinin A. In mice, we show that administration of neurokinin A diminishes MrgprB2 expression. Surprisingly, antagonism of the NK2R also downregulates MrgprB2 expression and in NK2R-deficient mice, MrgprB2 expression is markedly diminished. In contrast, co-administration of neurokinin A and a NK2R antagonist markedly increases MrgprB2 expression. In human skin explants, NK2R antagonism has minimal effect on MrgprX2 expression, but co-administration of neurokinin A and a NK2R antagonist upregulates MrgprX2 expression, as seen in murine skin. These data demonstrate that NK2R-signaling influences MrgprB2/X2 expression and, 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 dysregulated mast cell function initiated through the MrgprX2.