Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis

Shiqun Zhang, Tara N. Edwards, Virendra K. Chaudhri, Jianing Wu, Jonathan A. Cohen, Toshiro Hirai, Natalie Rittenhouse, Elizabeth G. Schmitz, Paul Yifan Zhou, Benjamin D. McNeil, Yi Yang, H. Richard Koerber, Tina L. Sumpter, Amanda C. Poholek, Brian M. Davis, Kathryn M. Albers, Harinder Singh, Daniel H. Kaplan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2151-2166.e16
Issue number8
StatePublished - Apr 15 2021


  • Langerhans cell
  • Mas-related G protein receptors
  • MrgprB2
  • MrgprD
  • S. aureus, beta-alanine
  • glutamate
  • kainate receptors
  • mast cell
  • neuroimmunology
  • nonpeptidergic neurons
  • skin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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