Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch

Immunity. 2019 May 21;50(5):1163-1171.e5. doi: 10.1016/j.immuni.2019.03.013. Epub 2019 Apr 23.


Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Keywords: GPCR; MRGPRX2; Mrgpr; Mrgprb2; histamine; itch; mast cell; pruritus; receptor.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Female
  • Histamine / metabolism
  • Histamine Antagonists / therapeutic use
  • Humans
  • Immunoglobulin E / immunology
  • Male
  • Mast Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Nerve Tissue Proteins / metabolism*
  • Peptide Fragments / metabolism
  • Pruritus / pathology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, IgE / metabolism*
  • Receptors, Neuropeptide / metabolism*
  • Serotonin / metabolism
  • Skin / metabolism
  • Tryptases / metabolism
  • Young Adult


  • Histamine Antagonists
  • MRGPRX2 protein, human
  • Mrgprb2 protein, mouse
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • Receptors, IgE
  • Receptors, Neuropeptide
  • Serotonin
  • Immunoglobulin E
  • Histamine
  • Tryptases