@article{584b2d847a2942f2ab8e97c18b759dc7,
title = "MrgprA3-expressing pruriceptors drive pruritogen-induced alloknesis through mechanosensitive Piezo2 channel",
abstract = "Although touch and itch are coded by distinct neuronal populations, light touch also provokes itch in the presence of exogenous pruritogens, resulting in a phenomenon called alloknesis. However, the cellular and molecular mechanisms underlying the initiation of pruritogen-induced mechanical itch sensitization are poorly understood. Here, we show that intradermal injections of histamine or chloroquine (CQ) provoke alloknesis through activation of TRPV1- and MrgprA3-expressing prurioceptors, and functional ablation of these neurons reverses pruritogen-induced alloknesis. Moreover, genetic ablation of mechanosensitive Piezo2 channel function from MrgprA3-expressing prurioceptors also dampens pruritogen-induced alloknesis. Mechanistically, histamine and CQ sensitize Piezo2 channel function, at least in part, through activation of the phospholipase C (PLC) and protein kinase C-δ (PKCδ) signaling. Collectively, our data find a TRPV1+/MrgprA3+ prurioceptor-Piezo2 signaling axis in the initiation of pruritogen-induced mechanical itch sensitization in the skin.",
keywords = "CP: Neuroscience, PKCδ, PLC, Piezo2, alloknesis, pruriceptor, pruritogens",
author = "Ping Lu and Yonghui Zhao and Zili Xie and Huan Zhou and Xinzhong Dong and Wu, {Gregory F.} and Kim, {Brian S.} and Jing Feng and Hongzhen Hu",
note = "Funding Information: We thank Dr. Mark Hoon for sharing the Trpv1Cre mice and Dr. Xinzhong Dong for sharing the MrgprA3 GFP-Cre mouse line. This work is supported by National Institutes of Health grants R01AA027065 , R01AR077183 , and R01DK103901 to H.H. and R01NS106289 to G.F.W. Funding Information: We thank Dr. Mark Hoon for sharing the Trpv1Cre mice and Dr. Xinzhong Dong for sharing the MrgprA3GFP-Cre mouse line. This work is supported by National Institutes of Health grants R01AA027065, R01AR077183, and R01DK103901 to H.H. and R01NS106289 to G.F.W. H.H. and J.F. conceived the project and wrote the manuscript. P.L. designed and conducted most of mouse behavioral experiments. P.L. and Y.Z. were responsible for RNAscope and immunostaining. Y.Z. and Z.X. were responsible for patch-clamp recordings. Others assisted with the data analysis and manuscript preparation. B.S.K. has served as a consultant for AbbVie, Almirall S.A. Amagma, Argenx, Astra Zeneca, Bellus Health, Blueprint Medicines, Boehringer Ingelheim Corporation, Bristol-Myers Squibb, Cara Therapeutics, Daewoong Pharmaceutical, Eli Lilly and Company, Guidepoint Global, Janssen Pharmaceuticals, Incyte Corporation, Kiniksa Pharmaceuticals, LectureLinx, LEO Pharma, Maruho, Novartis, OM Pharma, Pfizer, Sanofi Genzyme, Shaperon, Third Rock Ventures, and Trevi Therapeutics; is a stockholder of Recens Medical and Locus Biosciences; and serves on the scientific advisory boards for Abrax Japan, Granular Therapeutics, Recens Medical, National Eczema Association, Cell Reports Medicine, and Journal of Allergy and Clinical Immunology. B.S.K. is an inventor on a patent/patent application (WO2017143014A1) held/submitted by Washington University that covers the use of JAK inhibitors for chronic pruritus. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = apr,
day = "25",
doi = "10.1016/j.celrep.2023.112283",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}