MRGPRX4 is a bile acid receptor for human cholestatic itch

  1. Huasheng Yu
  2. Tianjun Zhao
  3. Simin Liu
  4. Qinxue Wu
  5. Omar Johnson
  6. Zhaofa Wu
  7. Zihao Zhuang
  8. Yaocheng Shi
  9. Luxin Peng
  10. Renxi He
  11. Yong Yang
  12. Jianjun Sun
  13. Xiaoqun Wang
  14. Haifeng Xu
  15. Zheng Zeng
  16. Peng Zou
  17. Xiaoguang Lei
  18. Wenqin Luo  Is a corresponding author
  19. Yulong Li  Is a corresponding author
  1. Peking University School of Life Sciences, China
  2. University of Pennsylvania, United States
  3. Peking University, China
  4. Peking University First Hospital, China
  5. Peking University Third Hospital, China
  6. Chinese Academy of Sciences, China
  7. Peking Union Medical College Hospital, China
  8. Peking-Tsinghua Center for Life Sciences, China

Abstract

Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca2+ responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Huasheng Yu

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5641-2512
  2. Tianjun Zhao

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Simin Liu

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Qinxue Wu

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Omar Johnson

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Zhaofa Wu

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Zihao Zhuang

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Yaocheng Shi

    Department of Chemical Biology, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Luxin Peng

    Department of Chemical Biology, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Renxi He

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Yong Yang

    Department of Dermatology, Peking University First Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Jianjun Sun

    Department of Neurosurgery, Peking University Third Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Xiaoqun Wang

    State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Haifeng Xu

    Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Zheng Zeng

    Department of Infectious Diseases, Peking University First Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Peng Zou

    Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9798-5242
  17. Xiaoguang Lei

    Peking-Tsinghua Center for Life Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Wenqin Luo

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    luow@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2486-807X
  19. Yulong Li

    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
    For correspondence
    yulongli@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9166-9919

Funding

Department of the Central Committee of the CPC (Junior Thousand Talents Program of China)

  • Yulong Li

Chinese Institute for Brain Research (Z181100001518004)

  • Yulong Li

University of Pennsylvania (Internal funding)

  • Wenqin Luo

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

Ethics

Human subjects: All experiments involving human subjects have been approved by institutional review board or ethics committee and the informed consent, and consent to publish, was obtained. Collection of DRG tissue from adult humans was approved by the Committee for Medical Science Research Ethics, Peking University Third Hospital (IRB00006761-2015238), and collection from human embryos was approved by the Reproductive Study Ethics Committee of Peking University Third Hospital (2012SZ-013 and 2017SZ-043) and Beijing Anzhen Hospital (2014012x). The human itch test studies were approved by the Committee for Protecting Human and Animal Subjects at the Department of Psychology, Peking University (#2018-05-02). Collection of blood samples from patients were approved by the Committee for Biomedical Ethics, Peking University First Hospital (2017-R-94).

Reviewing Editor

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

Publication history

  1. Received: May 13, 2019
  2. Accepted: September 2, 2019
  3. Accepted Manuscript published: September 10, 2019 (version 1)
  4. Version of Record published: October 1, 2019 (version 2)
  5. Version of Record updated: October 8, 2019 (version 3)

Copyright

© 2019, Yu 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. Huasheng Yu
  2. Tianjun Zhao
  3. Simin Liu
  4. Qinxue Wu
  5. Omar Johnson
  6. Zhaofa Wu
  7. Zihao Zhuang
  8. Yaocheng Shi
  9. Luxin Peng
  10. Renxi He
  11. Yong Yang
  12. Jianjun Sun
  13. Xiaoqun Wang
  14. Haifeng Xu
  15. Zheng Zeng
  16. Peng Zou
  17. Xiaoguang Lei
  18. Wenqin Luo
  19. Yulong Li
(2019)
MRGPRX4 is a bile acid receptor for human cholestatic itch
eLife 8:e48431.
https://doi.org/10.7554/eLife.48431

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