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Papers: 20 Mar 2021 - 26 Mar 2021


2021 Mar 18


Cell

Editor's Pick

Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.

Authors

Zhang S, Edwards TN, Chaudhri VK, Wu J, Cohen JA, Hirai T, Rittenhouse N, Schmitz EG, Zhou P Y, McNeil BD, Yang Y, Koerber RH, Sumpter TL, Poholek AC, Davis BM, Albers KM, Singh H, Kaplan DH
Cell. 2021 Mar 18.
PMID: 33765440.

Abstract

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.