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Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis

Zhang, S;Edwards, TN;Chaudhri, VK;Wu, J;Cohen, JA;Hirai, T;Rittenhouse, N;Schmitz, EG;Zhou, PY;McNeil, BD;Yang, Y;Koerber, HR;Sumpter, TL;Poholek, AC;Davis, BM;Albers, KM;Singh, H;Kaplan, DH;

Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.