ChloroquineV1, Ncbi, Merge, bibRecord, 000A09

MRGPRX4 is a bile acid receptor for human cholestatic itch

Identifieur interne : 000A09 ( Ncbi/Merge ); précédent : 000A08; suivant : 000A10

MRGPRX4 is a bile acid receptor for human cholestatic itch

Source :

eLife [ 2050-084X ] ; ????.

RBID : PMC:6773440

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773440

DOI: 10.7554/eLife.48431
PubMed: 31500698
PubMed Central: 6773440

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PMC:6773440

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">MRGPRX4 is a bile acid receptor for human cholestatic itch</title>
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<author><name sortKey="Wu, Zhaofa" sort="Wu, Zhaofa" uniqKey="Wu Z" first="Zhaofa" last="Wu">Zhaofa Wu</name>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Zhuang, Zihao" sort="Zhuang, Zihao" uniqKey="Zhuang Z" first="Zihao" last="Zhuang">Zihao Zhuang</name>
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<addr-line>Beijing</addr-line>
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</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Shi, Yaocheng" sort="Shi, Yaocheng" uniqKey="Shi Y" first="Yaocheng" last="Shi">Yaocheng Shi</name>
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<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Peng, Luxin" sort="Peng, Luxin" uniqKey="Peng L" first="Luxin" last="Peng">Luxin Peng</name>
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<institution>Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="He, Renxi" sort="He, Renxi" uniqKey="He R" first="Renxi" last="He">Renxi He</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">State Key Laboratory of Membrane Biology</institution>
<institution>Peking University School of Life Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>PKU-IDG/McGovern Institute for Brain Research</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yang, Yong" sort="Yang, Yong" uniqKey="Yang Y" first="Yong" last="Yang">Yong Yang</name>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution content-type="dept">Department of Dermatology, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses</institution>
<institution>Peking University First Hospital, Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sun, Jianjun" sort="Sun, Jianjun" uniqKey="Sun J" first="Jianjun" last="Sun">Jianjun Sun</name>
<affiliation wicri:level="1"><nlm:aff id="aff7"><institution content-type="dept">Department of Neurosurgery</institution>
<institution>Peking University Third Hospital, Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wang, Xiaoqun" sort="Wang, Xiaoqun" uniqKey="Wang X" first="Xiaoqun" last="Wang">Xiaoqun Wang</name>
<affiliation wicri:level="1"><nlm:aff id="aff8"><institution content-type="dept">State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics</institution>
<institution>Chinese Academy of Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Xu, Haifeng" sort="Xu, Haifeng" uniqKey="Xu H" first="Haifeng" last="Xu">Haifeng Xu</name>
<affiliation wicri:level="1"><nlm:aff id="aff9"><institution content-type="dept">Department of Liver Surgery</institution>
<institution>Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zeng, Zheng" sort="Zeng, Zheng" uniqKey="Zeng Z" first="Zheng" last="Zeng">Zheng Zeng</name>
<affiliation wicri:level="1"><nlm:aff id="aff10"><institution content-type="dept">Department of Infectious Diseases</institution>
<institution>Peking University First Hospital</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zou, Peng" sort="Zou, Peng" uniqKey="Zou P" first="Peng" last="Zou">Peng Zou</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution content-type="dept">Department of Chemical Biology, College of Chemistry and Molecular Engineering</institution>
<institution>Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lei, Xiaoguang" sort="Lei, Xiaoguang" uniqKey="Lei X" first="Xiaoguang" last="Lei">Xiaoguang Lei</name>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Peking-Tsinghua Center for Life Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution content-type="dept">Department of Chemical Biology, College of Chemistry and Molecular Engineering</institution>
<institution>Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Luo, Wenqin" sort="Luo, Wenqin" uniqKey="Luo W" first="Wenqin" last="Luo">Wenqin Luo</name>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution content-type="dept">Department of Neuroscience, Perelman School of Medicine</institution>
<institution>University of Pennsylvania</institution>
<addr-line>Philadelphia</addr-line>
<country>United States</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Li, Yulong" sort="Li, Yulong" uniqKey="Li Y" first="Yulong" last="Li">Yulong Li</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">State Key Laboratory of Membrane Biology</institution>
<institution>Peking University School of Life Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>PKU-IDG/McGovern Institute for Brain Research</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Peking-Tsinghua Center for Life Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Chinese Institute for Brain Research</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">eLife</title>
<idno type="eISSN">2050-084X</idno>
<imprint><date when="????">????</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><p>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 Ca<sup>2+</sup>
 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.</p>
</div>
</front>
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  <front><journal-meta><journal-id journal-id-type="nlm-ta">eLife</journal-id>
<journal-id journal-id-type="iso-abbrev">Elife</journal-id>
<journal-id journal-id-type="publisher-id">eLife</journal-id>
<journal-title-group><journal-title>eLife</journal-title>
</journal-title-group>
<issn pub-type="epub">2050-084X</issn>
<publisher><publisher-name>eLife Sciences Publications, Ltd</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31500698</article-id>
<article-id pub-id-type="pmc">6773440</article-id>
<article-id pub-id-type="publisher-id">48431</article-id>
<article-id pub-id-type="doi">10.7554/eLife.48431</article-id>
<article-categories><subj-group subj-group-type="display-channel"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Neuroscience</subject>
</subj-group>
</article-categories>
<title-group><article-title>MRGPRX4 is a bile acid receptor for human cholestatic itch</article-title>
</title-group>
<contrib-group><contrib id="author-142046" contrib-type="author"><name><surname>Yu</surname>
<given-names>Huasheng</given-names>
</name>
<contrib-id authenticated="true" contrib-id-type="orcid">https://orcid.org/0000-0001-5641-2512</contrib-id>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="fn" rid="con1"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142047" contrib-type="author"><name><surname>Zhao</surname>
<given-names>Tianjun</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
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</contrib>
<contrib id="author-142055" contrib-type="author"><name><surname>Liu</surname>
<given-names>Simin</given-names>
</name>
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<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142056" contrib-type="author"><name><surname>Wu</surname>
<given-names>Qinxue</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="fn" rid="con4"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142057" contrib-type="author"><name><surname>Johnson</surname>
<given-names>Omar</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="fn" rid="con5"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142058" contrib-type="author"><name><surname>Wu</surname>
<given-names>Zhaofa</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="fn" rid="con6"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142059" contrib-type="author"><name><surname>Zhuang</surname>
<given-names>Zihao</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="fn" rid="con7"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142060" contrib-type="author"><name><surname>Shi</surname>
<given-names>Yaocheng</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
<xref ref-type="fn" rid="con8"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-154333" contrib-type="author"><name><surname>Peng</surname>
<given-names>Luxin</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
<xref ref-type="fn" rid="con9"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142061" contrib-type="author"><name><surname>He</surname>
<given-names>Renxi</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="fn" rid="con10"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-22536" contrib-type="author"><name><surname>Yang</surname>
<given-names>Yong</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
<xref ref-type="fn" rid="con11"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142062" contrib-type="author"><name><surname>Sun</surname>
<given-names>Jianjun</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
<xref ref-type="fn" rid="con12"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-47065" contrib-type="author"><name><surname>Wang</surname>
<given-names>Xiaoqun</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
<xref ref-type="fn" rid="con13"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142063" contrib-type="author"><name><surname>Xu</surname>
<given-names>Haifeng</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
<xref ref-type="fn" rid="con14"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-142647" contrib-type="author"><name><surname>Zeng</surname>
<given-names>Zheng</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
<xref ref-type="fn" rid="con15"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-58655" contrib-type="author"><name><surname>Zou</surname>
<given-names>Peng</given-names>
</name>
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-9798-5242</contrib-id>
<xref ref-type="aff" rid="aff5">5</xref>
<xref ref-type="fn" rid="con16"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-46187" contrib-type="author"><name><surname>Lei</surname>
<given-names>Xiaoguang</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff5">5</xref>
<xref ref-type="fn" rid="con17"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-18016" contrib-type="author" corresp="yes"><name><surname>Luo</surname>
<given-names>Wenqin</given-names>
</name>
<contrib-id authenticated="true" contrib-id-type="orcid">https://orcid.org/0000-0002-2486-807X</contrib-id>
<email>luow@pennmedicine.upenn.edu</email>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="other" rid="fund3"></xref>
<xref ref-type="fn" rid="con18"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<contrib id="author-118965" contrib-type="author" corresp="yes"><name><surname>Li</surname>
<given-names>Yulong</given-names>
</name>
<contrib-id authenticated="true" contrib-id-type="orcid">https://orcid.org/0000-0002-9166-9919</contrib-id>
<email>yulongli@pku.edu.cn</email>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff11">11</xref>
<xref ref-type="other" rid="fund1"></xref>
<xref ref-type="other" rid="fund2"></xref>
<xref ref-type="fn" rid="con19"></xref>
<xref ref-type="fn" rid="conf1"></xref>
</contrib>
<aff id="aff1"><label>1</label>
<institution content-type="dept">State Key Laboratory of Membrane Biology</institution>
<institution>Peking University School of Life Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff2"><label>2</label>
<institution>PKU-IDG/McGovern Institute for Brain Research</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff3"><label>3</label>
<institution>Peking-Tsinghua Center for Life Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff4"><label>4</label>
<institution content-type="dept">Department of Neuroscience, Perelman School of Medicine</institution>
<institution>University of Pennsylvania</institution>
<addr-line>Philadelphia</addr-line>
<country>United States</country>
</aff>
<aff id="aff5"><label>5</label>
<institution content-type="dept">Department of Chemical Biology, College of Chemistry and Molecular Engineering</institution>
<institution>Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff6"><label>6</label>
<institution content-type="dept">Department of Dermatology, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses</institution>
<institution>Peking University First Hospital, Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff7"><label>7</label>
<institution content-type="dept">Department of Neurosurgery</institution>
<institution>Peking University Third Hospital, Peking University</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff8"><label>8</label>
<institution content-type="dept">State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics</institution>
<institution>Chinese Academy of Sciences</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff9"><label>9</label>
<institution content-type="dept">Department of Liver Surgery</institution>
<institution>Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff10"><label>10</label>
<institution content-type="dept">Department of Infectious Diseases</institution>
<institution>Peking University First Hospital</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
<aff id="aff11"><label>11</label>
<institution>Chinese Institute for Brain Research</institution>
<addr-line>Beijing</addr-line>
<country>China</country>
</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Ginty</surname>
<given-names>David D</given-names>
</name>
<role>Reviewing Editor</role>
<aff><institution>Harvard Medical School</institution>
<country>United States</country>
</aff>
</contrib>
<contrib contrib-type="editor"><name><surname>Westbrook</surname>
<given-names>Gary L</given-names>
</name>
<role>Senior Editor</role>
<aff><institution>Oregon Health and Science University</institution>
<country>United States</country>
</aff>
</contrib>
</contrib-group>
<pub-date date-type="pub" publication-format="electronic"><day>10</day>
<month>9</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>8</volume>
<elocation-id>e48431</elocation-id>
<history><date date-type="received" iso-8601-date="2019-05-13"><day>13</day>
<month>5</month>
<year>2019</year>
</date>
<date date-type="accepted" iso-8601-date="2019-09-02"><day>02</day>
<month>9</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019, Yu et al</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>Yu et al</copyright-holder>
<ali:free_to_read></ali:free_to_read>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><ali:license_ref>http://creativecommons.org/licenses/by/4.0/</ali:license_ref>
<license-p>This article is distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use and redistribution provided that the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="elife-48431.pdf"></self-uri>
<abstract><p>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 Ca<sup>2+</sup>
 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.</p>
</abstract>
<kwd-group kwd-group-type="author-keywords"><kwd>MRGPRX4</kwd>
<kwd>bile acids</kwd>
<kwd>orphan GPCR</kwd>
<kwd>chronic itch</kwd>
<kwd>cholestasis</kwd>
</kwd-group>
<kwd-group kwd-group-type="research-organism"><title>Research organism</title>
<kwd>Human</kwd>
</kwd-group>
<funding-group><award-group id="fund1"><funding-source><institution-wrap><institution>Department of the Central Committee of the CPC</institution>
</institution-wrap>
</funding-source>
<award-id>Junior Thousand Talents Program of China</award-id>
<principal-award-recipient><name><surname>Li</surname>
<given-names>Yulong</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="fund2"><funding-source><institution-wrap><institution>Chinese Institute for Brain Research</institution>
</institution-wrap>
</funding-source>
<award-id>Z181100001518004</award-id>
<principal-award-recipient><name><surname>Li</surname>
<given-names>Yulong</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="fund3"><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100006920</institution-id>
<institution>University of Pennsylvania</institution>
</institution-wrap>
</funding-source>
<award-id>Internal funding</award-id>
<principal-award-recipient><name><surname>Luo</surname>
<given-names>Wenqin</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.</funding-statement>
</funding-group>
<custom-meta-group><custom-meta specific-use="meta-only"><meta-name>Author impact statement</meta-name>
<meta-value>Bile acid and it's receptor MRGPRX4, but not TGR5, is one of the ligand-receptor pairs for chronic itch in patients with liver diseases.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<sub-article id="SA1" article-type="decision-letter"><front-stub><article-id pub-id-type="doi">10.7554/eLife.48431.025</article-id>
<title-group><article-title>Decision letter</article-title>
</title-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Ginty</surname>
<given-names>David D</given-names>
</name>
<role>Reviewing Editor</role>
<aff><institution>Harvard Medical School</institution>
<country>United States</country>
</aff>
</contrib>
<contrib contrib-type="reviewer"><name><surname>Bautista</surname>
<given-names>Diana M</given-names>
</name>
<role>Reviewer</role>
<aff><institution>University of California, Berkeley</institution>
<country>United States</country>
</aff>
</contrib>
</contrib-group>
</front-stub>
<body><boxed-text position="float" orientation="portrait"><p>In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.</p>
</boxed-text>
<p>Thank you for submitting your article "MRGPRX4 is a novel bile acid receptor in cholestatic itch" for consideration by <italic>eLife</italic>
. Your article has been reviewed by three peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Gary Westbrook as the Senior Editor. The following individual involved in review of your submission has agreed to reveal their identity: Diana M Bautista (Reviewer #3). The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.</p>
<p>Summary:</p>
<p>In this work by Yu and colleagues, the authors examine the important question of why patients with liver disease often times develop cholestatic pruritus. Previous studies have shown that bile acids can trigger acute itch in mice via TGR5 signaling in a subset of mouse DRG neurons (Alemi et al., 2013) and that MRGPRX4 is activated by bilirubin (Meixiong et al., 2019) and bile acids (Meixiong et al, 2019). Here the authors probe the molecular mechanisms by which bile acids promote itch in human subjects and DRG neurons. To address the specific receptor for itch-inducing substances, they examined orphan G-protein coupled receptors that are highly expressed in human sensory afferents identified via public expression databases. Specifically, they identified 7 highly expressed GPCRs which they expressed in heterologous cells and assayed for sensitivity to bile extracts using G-protein coupled assays.</p>
<p>In this approach they focused on MRGPRX4 as a candidate receptor because of its lone sensitivity to bile acids in a Gq-dependent assay. Although this is a significant finding, as the authors point out, MRGPRX4 was recently shown by Meixiong et al. to be activated by bile acids and lead to itch when the human receptor was expressed in mice. Nonetheless, the authors expand upon these and other previous findings to fully define the role of Mrgprx4 in human tissues, as well as identify the specific ligands that may act on this receptor to induce itch. They show that bile acids are more robust activators of MRGPRX4, and itch in human subjects, compared to bilirubin, and that bilirubin potentiates bile acid activation of MRGPRX4. The inclusion of human and primate assays is a strength, as are their findings suggesting a difference in Mrgprx4 function and expression in human versus rodent dorsal root ganglia. Overall this is a comprehensive and well done study that will be of importance to the field.</p>
<p>Essential revisions:</p>
<p>1) In Figure 2B the authors focus on fractions 4 and 6 when clearly fractions 2, 3, and 5 have high activity. It is unclear why this was done. Can the authors examine the potential for itch inducing substances in these fractions, or at least confirm that the relevant compound DCA found in fraction 4 is also in these other active fractions?</p>
<p>2) In Figure 3K the expression of the P180A mutant is clearly 3-fold higher than the other mutants, a point that should be evaluated or discussed.</p>
<p>3) In addition to the RNAscope representative images in Figure 4F, some examples of the entire section should be displayed showing colocalization of MRGPRX4 with other genes as this is the main method used to define the MRGPRX4 neuronal population.</p>
<p>4) It's unclear how the representative Fluo-8 images in Figure 4H, left panel, are related to the small pseudocolor images under the traces Figure 4H, right panel. Full pseudocolor images of the DRGs with and without bile acids should be included (same as the format of Figure 4H, left panel).</p>
<p>5) In prior work, bilirubin was shown to not only trigger calcium influx via MRGPRX4 but also action potential firing in rodent neurons. Does bile acid activation of MRGPRX4 drive excitability of DRG neurons? Since the manuscript only reports relative fluo-8 fluorescence changes, the magnitudes of the bile-acid evoked calcium responses in neurons are unknown. Please discuss this point.</p>
<p>6) Do adult and embryonic DRG neurons display similar MRGPRX4 expression patterns and bile acid responses? Is the data currently pooled in the summary figures? If so, some statistical analyses should be performed to ensure there are no age-specific differences before combining the data.</p>
<p>7) The bilirubin modulation data should be included as a main figure in the manuscript.</p>
<p>8) What antibodies and criteria were used to define satellite glia cells in the IHC experiments? Please provide this information.</p>
<p>9) The title should be changed to avoid the word "novel" because MRGPRX4 has already been implicated as a receptor that mediates cholestatic itch.</p>
</body>
</sub-article>
<sub-article id="SA2" article-type="reply"><front-stub><article-id pub-id-type="doi">10.7554/eLife.48431.026</article-id>
<title-group><article-title>Author response</article-title>
</title-group>
</front-stub>
<body><disp-quote content-type="editor-comment"><p>Essential revisions:</p>
<p>1) In Figure 2B the authors focus on fractions 4 and 6 when clearly fractions 2, 3, and 5 have high activity. It is unclear why this was done. Can the authors examine the potential for itch inducing substances in these fractions, or at least confirm that the relevant compound DCA found in fraction 4 is also in these other active fractions?</p>
</disp-quote>
<p>We thank the reviewer for raising this question. We have noticed that the fractions 2, 3 and 5 also have high activity. Using <sup>1</sup>
H-NMR, we found that fractions 2, 3 also contained the characteristic peaks of bile acids (Figure 2—figure supplement 1), suggesting that the activity may come from the bile acids in these fractions. Due to the limited amount of material, we haven’t been able to test fraction 5 using <sup>1</sup>
H-NMR, but we suspect the activity of this fraction may also come from bile acids. We modified text to explain this point in the revised manuscript.</p>
<disp-quote content-type="editor-comment"><p>2) In Figure 3K the expression of the P180A mutant is clearly 3-fold higher than the other mutants, a point that should be evaluated or discussed.</p>
</disp-quote>
<p>We thank the reviewer for noticing this finding. In this experiment, we generated stable cell lines expressing wild-type and mutant receptors via piggyBac transposon system. The gene is randomly inserted into the genome of the HEK293T cell lines. Thus, both insertion sites and copy numbers could significantly affect the expression level. The P180A mutant gene might be inserted into a favorable genomic site or multiple copies of the gene might be inserted into the genome, which leads to much higher membrane expression level than WT. Nevertheless, P180A mutant still shows less response to DCA. We hope reviewers could agree that P180 in MRGPRX4 is an important amino acid residue for bile acid sensing. We have added the discussion to the manuscript as the reviewer suggested.</p>
<disp-quote content-type="editor-comment"><p>3) In addition to the RNAscope representative images in Figure 4F, some examples of the entire section should be displayed showing colocalization of MRGPRX4 with other genes as this is the main method used to define the MRGPRX4 neuronal population.</p>
</disp-quote>
<p>We thank the reviewer for the good suggestion. There is a technical reason we didn’t include the low magnification pictures in the initial submission. MRGPRX4 signals in most positive DRG neurons are rather weak (have ~20 small fluorescent dots, indicated by arrow heads in <xref ref-type="fig" rid="respfig1">Author response image 1</xref>
 and as shown in the Figure 4F of the main text), and it is hard to tell a real positive neuron from background (big fluorescent dots positive for all three channels (indicated by arrows), which unfortunately exist for RNAscope in situ technique, especially for the weak probe channel) at the low magnification (<xref ref-type="fig" rid="respfig1">Author response image 1</xref>
 upper row). We thus mostly took high magnification images to be sure. Therefore, we have included a large-scale image of the DRG section, in which triple RNAscope in situ hybridization of <italic>TRPV1, H1R1</italic>
, and <italic>MRGPRX4</italic>
 were performed (<xref ref-type="fig" rid="respfig1">Author response image 1</xref>
). As the reviewers can see, the TRPV1+ (usually more than 100 positive dots per cells) and H1R1+ (usually more than 50 to 100 positive dots per cells) neurons are easy to tell (indicated by arrowheads), but it is much harder to tell positive MRGRPX4+ neurons at this low magnification.</p>
<fig id="respfig1" orientation="portrait" position="float"><object-id pub-id-type="doi">10.7554/eLife.48431.024</object-id>
<label>Author response image 1.</label>
<caption><title>Representative large-scale RNAscope images of human DRG.</title>
<p>Each fluorescent dot indicated by an arrowhead represents one single mRNA transcript. The large fluorescent dots indicated by arrows are non-specific background (positive for all three channels). Scale bar, 100 μm and 50 μm.</p>
</caption>
<graphic xlink:href="elife-48431-resp-fig1"></graphic>
</fig>
<disp-quote content-type="editor-comment"><p>4) It's unclear how the representative Fluo-8 images in Figure 4H, left panel, are related to the small pseudocolor images under the traces Figure 4H, right panel. Full pseudocolor images of the DRGs with and without bile acids should be included (same as the format of Figure 4H, left panel).</p>
</disp-quote>
<p>We thank the reviewer for this good suggestion and we apologize for the unclear presentation. We have included a representative full pseudocolor image to show the responses of all imaged DRG neurons when applying DCA and other compounds (Figure 5G, Figure 5—figure supplement 2A). The circled cells on the left panel correspond to the representative traces and small pseudocolor images on the right panel.</p>
<disp-quote content-type="editor-comment"><p>5) In prior work, bilirubin was shown to not only trigger calcium influx via MRGPRX4 but also action potential firing in rodent neurons. Does bile acid activation of MRGPRX4 drive excitability of DRG neurons? Since the manuscript only reports relative fluo-8 fluorescence changes, the magnitudes of the bile-acid evoked calcium responses in neurons are unknown. Please discuss this point.</p>
</disp-quote>
<p>Since the expression percentage of MRGPRX4 is relatively low (6-7%) in human DRG neurons, and the quality of adult human DRG tissues from schwannoma patients, which were used for calcium imaging in this manuscript, are very limited, it is very difficult, if not impossible, to detect bile acid induced firing in the MRGPRX4-positive human DRG neurons. Alternatively, we electrically transfected MRGPRX4 in cultured rat DRG neurons and detected bile acid-induced action potentials of in MRGPRX4-expressing rat DRG neurons but not in non-transfected control cells by electrophysiology (Figure 5E, F, Figure 5—figure supplement 1E, F), demonstrating that activation of MRGPRX4 by bile acid could drive excitability of DRG neurons. In addition, we compared the activity of bilirubin and DCA to MRGPRX4 in cultured rat DRG neurons. Similar to the results in HEK293T cells. DCA showed stronger activity than bilirubin as it induced larger Ca<sup>2+</sup>
 response both in amplitude and percentage in MRGPRX4-expressing neurons (Figure 9D-G). We have included these results in the revised manuscript.</p>
<disp-quote content-type="editor-comment"><p>6) Do adult and embryonic DRG neurons display similar MRGPRX4 expression patterns and bile acid responses? Is the data currently pooled in the summary figures? If so, some statistical analyses should be performed to ensure there are no age-specific differences before combining the data.</p>
</disp-quote>
<p>We thank the reviewer for raising this point and we apologize for the confusion. Given that the difficulties to obtain the human DRG tissues, we haven’t directly examined the MRGPRX4 expression patterns in the embryonic DRG tissues. Nevertheless, the percentage (5.2%,Figure 5H) of cultured embryonic DRG neurons responding to bile acids is close to expression percentage (6-7%) of MRGPRX4 in the adult DRG tissues. For cultured adult DRG cells, the percentage responding to bile acids varied from batch to batch (3.3-18.2%, Figure 5—figure supplement 2D1-3). The adult DRG tissues are derived from schwannoma patients undergoing surgical excision (as described in the Materials and methods), so the different tissue qualities may contribute to the huge variability. We agree that it is not appropriate to combine the adult and embryonic data together for statistical analysis. We have statistically analyzed each culture separately (Figure 5G, HFigure 5—figure supplement 2) and revised our text to clarify this point.</p>
<disp-quote content-type="editor-comment"><p>7) The bilirubin modulation data should be included as a main figure in the manuscript.</p>
</disp-quote>
<p>Thank you for digging out and highlighting the bilirubin modulation data. We have included this part as a main figure (Figure 9).</p>
<disp-quote content-type="editor-comment"><p>8) What antibodies and criteria were used to define satellite glia cells in the IHC experiments? Please provide this information.</p>
</disp-quote>
<p>We mainly used morphological criteria to define human and monkey satellite glia cells. We tried immunostaining of a few antibodies (TLR4 for human and monkey satellite glia cells, HTA125, eBioscience; GPAP for mouse satellite glia cells, GFAP, AB_2313547 Aves Labs), which may stain satellite glia cells based on literatures<sup>1,2</sup>
, but none of them work for the human and monkey DRG satellite glia cells at our hand. This could be due to different tissue fixation and processing condition. We used fresh frozen for human DRGs, which works nicely for RNAscope in situ hybridization and antibody staining of MRGPRX4 and TGR5. Instead, we co-labeled human DRG neurons with NeuN antibody. We found that TGR5 immunostaining signal does not overlap with NeuN but surrounding these neurons and that TGR5 in situ signals also surround big negative DRG neuron soma. Given the size and morphology of satellite glia cells published before<sup>3</sup>
, we believe that the surrounded cells are satellite glia cells. Of course, if we had a good antibody to specifically label human/monkey satellite glia cells, we would be able to provide even stronger evidence.</p>
<disp-quote content-type="editor-comment"><p>9) The title should be changed to avoid the word "novel" because MRGPRX4 has already been implicated as a receptor that mediates cholestatic itch.</p>
</disp-quote>
<p>We agree that we should avoid the word “novel” in title since MRGPRX4 has already been implicated as a receptor that mediates cholestatic itch. We change our title to “MRGPRX4 is a bile acid receptor for human cholestatic itch”.</p>
<p>References:</p>
<p>1) Mitterreiter, J. G. et al. Satellite glial cells in human trigeminal ganglia have a broad expression of functional Toll-like receptors. Eur J Immunol 47, 1181-1187, doi:10.1002/eji.201746989 (2017).</p>
<p>2) Prabhakar, A., Vujovic, D., Cui, L., Olson, W. & Luo, W. Leaky expression of channelrhodopsin-2 (ChR2) in Ai32 mouse lines. PLoS One 14, e0213326, doi:10.1371/journal.pone.0213326 (2019).</p>
<p>3) OpenStax Anatomy and Physiology. Version 8.25 edn, (2016).</p>
</body>
</sub-article>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Yu, Huasheng" sort="Yu, Huasheng" uniqKey="Yu H" first="Huasheng" last="Yu">Huasheng Yu</name>
</noRegion>
<name sortKey="He, Renxi" sort="He, Renxi" uniqKey="He R" first="Renxi" last="He">Renxi He</name>
<name sortKey="He, Renxi" sort="He, Renxi" uniqKey="He R" first="Renxi" last="He">Renxi He</name>
<name sortKey="Lei, Xiaoguang" sort="Lei, Xiaoguang" uniqKey="Lei X" first="Xiaoguang" last="Lei">Xiaoguang Lei</name>
<name sortKey="Lei, Xiaoguang" sort="Lei, Xiaoguang" uniqKey="Lei X" first="Xiaoguang" last="Lei">Xiaoguang Lei</name>
<name sortKey="Li, Yulong" sort="Li, Yulong" uniqKey="Li Y" first="Yulong" last="Li">Yulong Li</name>
<name sortKey="Li, Yulong" sort="Li, Yulong" uniqKey="Li Y" first="Yulong" last="Li">Yulong Li</name>
<name sortKey="Li, Yulong" sort="Li, Yulong" uniqKey="Li Y" first="Yulong" last="Li">Yulong Li</name>
<name sortKey="Li, Yulong" sort="Li, Yulong" uniqKey="Li Y" first="Yulong" last="Li">Yulong Li</name>
<name sortKey="Liu, Simin" sort="Liu, Simin" uniqKey="Liu S" first="Simin" last="Liu">Simin Liu</name>
<name sortKey="Peng, Luxin" sort="Peng, Luxin" uniqKey="Peng L" first="Luxin" last="Peng">Luxin Peng</name>
<name sortKey="Shi, Yaocheng" sort="Shi, Yaocheng" uniqKey="Shi Y" first="Yaocheng" last="Shi">Yaocheng Shi</name>
<name sortKey="Sun, Jianjun" sort="Sun, Jianjun" uniqKey="Sun J" first="Jianjun" last="Sun">Jianjun Sun</name>
<name sortKey="Wang, Xiaoqun" sort="Wang, Xiaoqun" uniqKey="Wang X" first="Xiaoqun" last="Wang">Xiaoqun Wang</name>
<name sortKey="Wu, Zhaofa" sort="Wu, Zhaofa" uniqKey="Wu Z" first="Zhaofa" last="Wu">Zhaofa Wu</name>
<name sortKey="Wu, Zhaofa" sort="Wu, Zhaofa" uniqKey="Wu Z" first="Zhaofa" last="Wu">Zhaofa Wu</name>
<name sortKey="Xu, Haifeng" sort="Xu, Haifeng" uniqKey="Xu H" first="Haifeng" last="Xu">Haifeng Xu</name>
<name sortKey="Yang, Yong" sort="Yang, Yong" uniqKey="Yang Y" first="Yong" last="Yang">Yong Yang</name>
<name sortKey="Yu, Huasheng" sort="Yu, Huasheng" uniqKey="Yu H" first="Huasheng" last="Yu">Huasheng Yu</name>
<name sortKey="Yu, Huasheng" sort="Yu, Huasheng" uniqKey="Yu H" first="Huasheng" last="Yu">Huasheng Yu</name>
<name sortKey="Zeng, Zheng" sort="Zeng, Zheng" uniqKey="Zeng Z" first="Zheng" last="Zeng">Zheng Zeng</name>
<name sortKey="Zhao, Tianjun" sort="Zhao, Tianjun" uniqKey="Zhao T" first="Tianjun" last="Zhao">Tianjun Zhao</name>
<name sortKey="Zhao, Tianjun" sort="Zhao, Tianjun" uniqKey="Zhao T" first="Tianjun" last="Zhao">Tianjun Zhao</name>
<name sortKey="Zhao, Tianjun" sort="Zhao, Tianjun" uniqKey="Zhao T" first="Tianjun" last="Zhao">Tianjun Zhao</name>
<name sortKey="Zhuang, Zihao" sort="Zhuang, Zihao" uniqKey="Zhuang Z" first="Zihao" last="Zhuang">Zihao Zhuang</name>
<name sortKey="Zou, Peng" sort="Zou, Peng" uniqKey="Zou P" first="Peng" last="Zou">Peng Zou</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Wu, Qinxue" sort="Wu, Qinxue" uniqKey="Wu Q" first="Qinxue" last="Wu">Qinxue Wu</name>
</noRegion>
<name sortKey="Johnson, Omar" sort="Johnson, Omar" uniqKey="Johnson O" first="Omar" last="Johnson">Omar Johnson</name>
<name sortKey="Luo, Wenqin" sort="Luo, Wenqin" uniqKey="Luo W" first="Wenqin" last="Luo">Wenqin Luo</name>
</country>
</tree>
</affiliations>
</record>

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MRGPRX4 is a bile acid receptor for human cholestatic itch

MRGPRX4 is a bile acid receptor for human cholestatic itch

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