SUMMARY
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 through activation of the PLC-PKCδ signaling. Collectively, our data uncovered a TRPV1+/MrgprA3+ prurioceptor-Piezo2 signaling axis in the initiation of pruritogen-induced mechanical itch sensitization in the skin.
Competing Interest Statement
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; 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 patent/patent application (WO2017143014A1) held/submitted by Washington University that covers the use of JAK inhibitors for chronic pruritus.
Footnotes
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