Nonpeptidergic MrgprD-expressing neurons maintain cutaneous homeostasis via glutamate-mediated mast cell suppression

Cutaneous mast cells (MC) mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We found that Langerhans cell (LC)-deficient mice have reduced numbers of MrgprD-expressing epidermal nerve endings and manifest enhanced irritant dermatitis due to exaggerated MC degranulation. Ablation of LC or MrgprD-expressing neurons increased expression of a MC gene module including the activating receptor, Mrgprb2, resulting in increased MC degranulation and cutaneous inflammation in multiple models. β-alanine agonism of MrgprD-expressing neurons reduced expression of MC module genes and suppressed MC responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism and decreased in LC-deficient mice. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive MC and a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress MC hyperresponsiveness and skin inflammation via glutamate release thereby revealing an unexpected neuro-immune mechanism maintaining cutaneous immune homeostasis. For whole skin tissue RNAseq, mRNA was isolated from whole ear of DT treated MrgprdDTR mice, DT treated control MrgprdCre mice and WT mice treated with 50 mM β-ala or vehicle. For purified mast cell RNAseq, mRNA was extracted from sorted mast cells of DT treated MrgprdDTR and control MrgprdCre mice, or from peritoneal-derived mast cells cultured with 4 mM glutamate or 50 uM glutamate receptor anatognist NS102.