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.
Itch, the irritation we feel and the relief that comes from scratching, is an evolutionary warning system and defense against harmful environmental agents. Although once considered a subtype of pain, itch is now recognized as a unique sense, with its own distinct physiology and cell receptors. Here, we discuss recent advances in our understanding of itch and the molecular players that mediate this sensory modality.
A new study shows that astrocytes are involved in the development of chronic itch in a mouse model. This dependent on upregulation of lipocalin 2 (LCN2) by the transcription factor STAT-3 and astrogliosis.
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