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

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 explored, 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, 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.

Data availability

All data generated or analyzed during this study are included in the manuscript. Source data for main figures 1-7 have been provided.

Article and author information

Author details

  1. James Meixiong

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    James Meixiong, is a consultant for Escient Pharmaceuticals a company focused on developing small molecule inhibitors for MRGPRs.
  2. Chirag Vasavda

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Dustin Green

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Qin Zheng

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Lijun Qi

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. Shawn G Kwatra

    Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  7. James P Hamilton

    Department of Medicine, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Solomon H Snyder

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    For correspondence
    ssnyder1@jhmi.edu
    Competing interests
    No competing interests declared.
  9. Xinzhong Dong

    Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    For correspondence
    xdong2@jhmi.edu
    Competing interests
    Xinzhong Dong, has a financial interest in Escient Pharmaceuticals a company focused on developing small molecule inhibitors for MRGPRs.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9750-7718

Funding

National Institute of Neurological Disorders and Stroke (R01NS054791)

  • Xinzhong Dong

Howard Hughes Medical Institute

  • Xinzhong Dong

National Institute of Mental Health (MH18501)

  • Solomon H Snyder

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed in accordance with protocols approved by the Animal Care and Use Committee at the Johns Hopkins University School of Medicine. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols (MO16M40) of Johns Hopkins University.

Reviewing Editor

  1. David D Ginty, Harvard Medical School, United States

Publication history

  1. Received: December 3, 2018
  2. Accepted: January 17, 2019
  3. Accepted Manuscript published: January 18, 2019 (version 1)
  4. Accepted Manuscript updated: January 21, 2019 (version 2)
  5. Version of Record published: February 8, 2019 (version 3)

Copyright

© 2019, Meixiong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. James Meixiong
  2. Chirag Vasavda
  3. Dustin Green
  4. Qin Zheng
  5. Lijun Qi
  6. Shawn G Kwatra
  7. James P Hamilton
  8. Solomon H Snyder
  9. Xinzhong Dong
(2019)
Identification of a bilirubin receptor that may mediate a component of cholestatic itch
eLife 8:e44116.
https://doi.org/10.7554/eLife.44116

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