Neurokinin A blocks the ABCA1 channel to promote IL-10-dependent mast cell regulation

Abstract Cutaneous mast cells (MCs) reside in close proximity to peripheral sensory nerve fibers and are susceptible to regulation by neuropeptides. The tachykinin family member, Neurokinin A (NKA) binds with highest affinity to the Neurokinin 2 Receptor, expressed on MCs. MCs are poised to respond to NKA, but its role in the MC biology is, to our knowledge, under-explored. The objective of this study was to evaluate the effects of NKA on bone marrow (BM) MCs and peritoneal (P)MCs in vitro and in the murine model of passive cutaneous anaphylaxis (PCA) in vivo. Neurokinin A inhibited FceRI-initiated phosphorylation and nuclear localization of STAT5, and release of TNF and IL-13 in an IL-10-dependent manner. NKA affected the MC secretome, abrogating ABCA1-dependent release of the cysteine protease, calpain. Extracellular calpain, in turn, degraded IL-10. In vivo, NKA administration reduced PCA, inhibiting edema, and induction of inflammatory cytokines and in a manner that relied on MC derived-IL-10. Likewise, direct inhibition of the ABCA1 phenocopied the effects of NKA, reducing IgE-initiated MC responses in vitro and in vivo. In conclusion, NKA minimizes IgE-initiated inflammation though an IL-10-dependent mechanism and inhibits ABCA1-dependent release of the IL-10 degrading enzyme, calpain. This study illuminates a novel tier of neuropeptide mediated MC regulation through the ABCA1. Strategies interfering with the ABCA1 may be promising therapeutics for targeting MCs in cutaneous inflammatory diseases.