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

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

doi:10.7554/elife.44116

James Meixiong, Qin Zheng + Show 7 more

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https://doi.org/10.7554/elife.44116

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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.

Highlights

Chronic pruritus, or itch, is a complex and often debilitating symptom that accompanies a range of cutaneous and non-cutaneous diseases (Stander et al, 2007; Yosipovitch and Bernhard, 2013a)
The results reported by Meixiong, Vasavda et al suggest that drugs that prevent bilirubin from attaching to Mas-related G-protein Coupled Receptor (MRGPR) might help to alleviate jaundice-related itching
We hypothesized that Mas-related G-protein coupled receptor (Mrgpr)-cluster KO and A1 KO mice scratched less with a-napthyl isothiocyanate (ANIT) because MRGPRA1 mediates bilirubin-induced itch

Summary

Introduction

Itch, is a complex and often debilitating symptom that accompanies a range of cutaneous and non-cutaneous diseases (Stander et al, 2007; Yosipovitch and Bernhard, 2013a). Whereas injecting bilirubin into normal mice causes them to scratch, mice that have been genetically engineered to lack MRGPRs do not itch when their own bilirubin levels rise, or when they are injected with bilirubin or with plasma from patients who experience jaundice-related itching. The results reported by Meixiong, Vasavda et al suggest that drugs that prevent bilirubin from attaching to MRGPRs might help to alleviate jaundice-related itching. Yellowing of the skin, sclera, and mucosa due to abnormal accumulation of the yellow heme metabolite bilirubin, is commonly associated with chronic non-histaminergic pruritus. At highly elevated levels such as in cutaneous jaundice (>5 mg/dL, >85.5 mM bilirubin), it is associated with pruritus, a correlation first noted by physicians as early as the second century B.C.E. (Bassari and Koea, 2015)

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Materials and methods

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