@article{cbb75f2963104efaaf69efc33458bf17,
title = "Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch",
abstract = "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",
author = "James Meixiong and Michael Anderson and Nathachit Limjunyawong and Sabbagh, {Mark F.} and Eric Hu and Mack, {Madison R.} and Oetjen, {Landon K.} and Fang Wang and Kim, {Brian S.} and Xinzhong Dong",
note = "Funding Information: We thank Dr. Sze Yan Janelle Ho, Dr. Dustin Green, and Dr. Priyanka Pundir for helpful comments. This work was supported by NIH grants R01NS054791 and R01AI135186 (to X.D.), K08AR065577 (to B.S.K.), and R01AR070116 (to B.S.K.). B.S.K. is also supported by the American Skin Association and the Doris Duke Charitable Foundation . L.K.O. is supported by NHLBI grant T32HL007317 . M.R.M. is supported by NIAID grant T32AI007163 . This research was supported by Core A of the Penn Skin Biology and Diseases Resource-based Center, funded by 1P30AR069589-01 ( Millar ). Funding Information: We thank Dr. Sze Yan Janelle Ho, Dr. Dustin Green, and Dr. Priyanka Pundir for helpful comments. This work was supported by NIH grants R01NS054791 and R01AI135186 (to X.D.), K08AR065577 (to B.S.K.), and R01AR070116 (to B.S.K.). B.S.K. is also supported by the American Skin Association and the Doris Duke Charitable Foundation. L.K.O. is supported by NHLBI grant T32HL007317. M.R.M. is supported by NIAID grant T32AI007163. This research was supported by Core A of the Penn Skin Biology and Diseases Resource-based Center, funded by 1P30AR069589-01 (Millar). J.M. and X.D. conceptualized experiments. J.M. performed all experiments and analyzed the data with assistance from M.A. for in vivo imaging, N.L. for flow cytometry, M.F.S. for confocal imaging, and E.H. for mast cell release. M.R.M. L.K.O. F.W. and B.S.K. provided human skin samples, assisted with allergic contact dermatitis, and analyzed flow cytometry data. J.M. B.S.K. and X.D. wrote the manuscript with input from all authors. B.S.K. and X.D. supervised the project. J.M. is a consultant for Escient Pharmaceuticals, a company focused on developing small-molecule inhibitors for MRGPRs. X.D. is a co-founder of Escient Pharmaceuticals and has a patent on drug targeting of MRGPRX2. B.S.K. has served as a consultant to AbbVie, Concert Pharmaceuticals, Incyte Corporation, Menlo Therapeutics, and Pfizer; has served on advisory boards for Cara Therapeutics, Celgene Corporation, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Sanofi, and Theravance Biopharma; is a shareholder in Locus Biosciences and Nuogen Pharma; and is founder and chief scientific officer of Nuogen Pharma. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "21",
doi = "10.1016/j.immuni.2019.03.013",
language = "English (US)",
volume = "50",
pages = "1163--1171.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "5",
}