Identification of a bilirubin receptor that may mediate a component of cholestatic itch

James Meixiong, Chirag Vasavda, Dustin Green, Qin Zheng, Lijun Qi, Shawn G. Kwatra, James P. Hamilton, Solomon H. Snyder, Xinzhong Dong

Research output: Contribution to journalArticle

Abstract

Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.

Original languageEnglish (US)
Article numbere44116
JournaleLife
Volume8
DOIs
StatePublished - Jan 21 2019

Keywords

  • Mrgpr
  • bilirubin
  • cholestasis
  • itch
  • mouse
  • neuroscience
  • sensory neuron

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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