biostudies-literatureZhang SNational Eczema AssociationNINDS NIH HHSNational Institutes of HealthNIAMS NIH HHSNIH HHS2151-2166.e16https://www.ebi.ac.uk/biostudies/studies/S-EPMC8052305biostudies-literatureUnknown184(8)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 reCellNonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.PMC8052305S10 OD011925R01 AR077341R01 NS096705R01 AR069951R01 AR071720Wu JAlbers KMChaudhri VKSchmitz EGKoerber HRKaplan DHZhang SHirai TDavis BMCohen JAEdwards TNZhou PYPoholek ACMcNeil BDSingh HYang YRittenhouse NSumpter TLfalseNonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.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 re2021-01-01T00:00:00Z2021 Apr2025-04-29T11:28:06.289Z2025-04-06T19:54:56.358ZS-EPMC80523053376544010.1016/j.cell.2021.03.002