Journal Article

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

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

2019

Overview

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. Jaundice causes the skin to yellow as a result of a build-up of a pigment called bilirubin. Normally, bilirubin is made in the liver and removed from the body in digestive fluid called bile, but people with liver or gallbladder problems may end up with too much bilirubin that accumulates in their blood and skin. One side effect of jaundice is intense and uncontrollable itching. Researchers are not sure what causes this itching, and there are few treatments that help to relieve it. At the molecular level, itching sensations occur when compounds bind to particular receptors on the surface of nerve cells. One family of receptors that can trigger itch is called the Mas-related G-protein Coupled Receptor (MRGPR). Could one of these receptors trigger jaundice-related itching? Now, Meixiong, Vasavda et al. show that bilirubin binds to and activates MRGPRs to cause itch in mice. 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. Furthermore, removing bilirubin from the plasma of patients before it was injected into normal mice reduced the amount of itching that the mice felt. Overall, 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. However, researchers must first verify that bilirubin interacts with MRGPRs in people to cause itch. If bilirubin causes itch in people like in mice, scientists could then evaluate existing drugs or make new ones to prevent bilirubin from attaching to the MRGPRs.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animal models / Animals / Behavior / Bile / Bilirubin / Bilirubin - blood / Bilirubin - metabolism / Biliverdin / Biliverdin reductase / cholestasis / Cholestasis - complications / Cholestasis - metabolism / Drug dosages / Gallbladder diseases / Gene deletion / Humans / Hyperbilirubinemia / Hyperbilirubinemia - blood / Hyperbilirubinemia - enzymology / itch / Jaundice / Medicine / Metabolites / Mice / Mice, Knockout / Mrgpr / Neuroscience / Oxidation / Oxidoreductases Acting on CH-CH Group Donors - genetics / Pain / Plasma / Pruritus / Pruritus - enzymology / Pruritus - etiology / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / sensory neuron / Sensory neurons / Skin / Students / Yellowing