The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, United States.
Elife. 2019 Jan 21;8:e44116. doi: 10.7554/eLife.44116.
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 or , 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 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.
各种病理状况都会导致黄疸，即由于胆红素积累而导致皮肤发黄。黄疸患者通常会报告经历强烈的非组胺能瘙痒。尽管存在这种关联，但胆红素本身的致痒能力尚未被描述，也没有发现胆红素受体。在这里，我们证明生理病理水平的胆红素可兴奋外周瘙痒感觉神经元，并通过表达于主要感觉神经元中的 G 蛋白偶联受体家族 MRGPRs 引起瘙痒。胆红素结合并激活两种 MRGPR，即小鼠 MRGPRA1 和人类 MRGPRX4。在两种病理性高胆红素血症的小鼠模型中，我们表明，编码胆红素生成酶胆绿素还原酶的基因 或 的基因缺失可减轻瘙痒。同样，从高胆红素血症患者中分离的血浆在野生型动物中引起瘙痒，但在 动物中没有引起瘙痒。去除胆红素降低了患者血浆的致痒能力。基于这些数据，靶向 MRGPRs 是缓解黄疸相关瘙痒的一种有前途的策略。
