Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine

• DOI: 10.1053/j.gastro.2021.03.049
• Publication Date: 2021-04-02T15:07:55Z
• Authors: Yong Chen; Zi-Long Wang; Michele Yeo; Qiao-Juan Zhang; Ana E. López-Romero; Hui-Ping Ding; Xin Zhang; Qian Zeng; Sara L. Morales-L...; Carlene Moore; Ying-Ai Jin; Huang-He Yang; Johannes Morstein; Andrey Bortsov; Marcin Krawczyk; Frank Lammert; Manal Abdelmalek; Anna Mae Diehl; Piotr Milkiewicz; Andreas E. Kremer; Jennifer Y. Zhang; Andrea Nackley; Tony E. Reeves; Mei-Chuan Ko; Ru-Rong Ji; Tamara Rosenbaum; Wolfgang Liedtke
• Keywords: Lysophosphatidylcholine; Sensory neuron

Background & AimsLimited understanding of pruritus mechanisms in cholestatic liver diseases hinders development antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator pruritus.MethodsPruritogenicity lysophosphatidylcholine (LPC), LPA's precursor, was examined naïve mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 studied using genetic pharmacologic approaches, cultured keratinocytes, ion channel physiology, structural computational modeling. Activation pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from identified vitro ex vivo Ca2+ imaging assays. Sera patients with primary biliary cholangitis were used for measuring the levels LPC miR-146a.ResultsLPC robustly pruritic mice. skin keratinocytes essential LPC-induced itch mice cholestasis. Three-dimensional modeling, site-directed mutagenesis, function analysis suggested C-terminal motif binding activation. In activation induced extracellular release miR-146a, which activated TRPV1+ to cause itch. miR-146a both elevated sera correlated intensity. Moreover, also increased elicited primates.ConclusionsWe novel pruritogen that induces through epithelia-sensory neuron cross talk, whereby it directly activates TRPV4, rapidly releases activate skin-innervating neurons. Our findings support new concept skin, organ, playing critical role itch, beyond liver, peripheral neurons, central neural pathways supporting pruriception. Limited pruritus. Pruritogenicity miR-146a. We