Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis

Cell. 2021 Apr 15;184(8):2151-2166.e16. doi: 10.1016/j.cell.2021.03.002. Epub 2021 Mar 24.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dermatitis / metabolism
  • Dermatitis / pathology
  • Diphtheria Toxin / pharmacology
  • Disease Models, Animal
  • Female
  • Glutamic Acid / metabolism*
  • Integrin beta Chains / genetics
  • Integrin beta Chains / metabolism
  • Langerhans Cells / cytology
  • Langerhans Cells / drug effects
  • Langerhans Cells / metabolism
  • Mast Cells / cytology
  • Mast Cells / drug effects
  • Mast Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / metabolism*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Skin / metabolism*
  • Skin / pathology
  • beta-Alanine / chemistry
  • beta-Alanine / metabolism
  • beta-Alanine / pharmacology


  • Diphtheria Toxin
  • Integrin beta Chains
  • Mrgprb2 protein, mouse
  • Mrgprd protein, mouse
  • Receptors, G-Protein-Coupled
  • beta-Alanine
  • Glutamic Acid