Professor Yulong Li’s group and their collaborators reported the molecular mechanisms causing cholestatic itch
Patients with cholestatic liver diseases tend to experience itchy skin more often than those without the condition. Persistent itching can be uncomfortable and might lead to excessive scratching, which can cause infection, pain, and lassitude. These side effects can severely affect patients’ qualities of life and can even give rise to mental problems such as depression1. However, the molecular mechanisms causing cholestatic itch remain unclear, nor are there effective drugs or treatments to relieve this kind of itching.
To study the molecular mechanisms of cholestatic itch in human, and to provide potential new drug targets for anti-itch therapies, two research groups screened the orphan G protein-coupled receptors (GPCRs) that are highly expressed in human dorsal root ganglia (hDRG) tissues and identified the roles of bile acids and MRGPRX4 as the pruritogen and receptor respectively for human cholestatic itch. The study reported that MRGPRX4 is activated by bile acids and is expressed specifically in human dorsal root ganglia (hDRG). In situ hybridization and immunohistochemistry revealed that MRGPRX4 is expressed in ~7% of hDRG neurons and co-localizes with HRH1, a known itch-inducing GPCR. In the experiment, bile acids elicited a robust Ca2+ response in a subset of cultured hDRG neurons which are previously known to be activated by histamine via HRH1.
Additionally, intradermal injection of both bile acids and MRGPRX4 specific agonists induced significant itchy sensations in healthy human subjects. Moreover, they found that plasma bile acid levels are significantly higher in itchy liver disease patients, as compared with their non-itchy counterparts. For the former patient subjects, their plasma bile acid levels greatly decreased following itch-relief manipulations. This evidence based on human volunteers further supports that the increased level of bile acids in the plasma is sufficient to activate MRGPRX4 on hDRG neurons, which, in turn, mediates cholestatic itch.
Molecular mechanism of cholestatic itch
Importantly, they also found that the previously identified membrane bile acid receptor TGR5 does not mediate bile acid-induced itch in human, which is different from its role reported in mice2,3. Application of TGR5 specific agonists failed to elicit detectable itching in human subjects or a significant Ca2+ response in cultured hDRG neurons. In situ hybridization and immunohistochemistry revealed that, unlike mice, TGR5 is highly expressed in human satellite glial cells instead of in DRG neurons. These results indicate that TGR5 is not a direct receptor that mediates bile acid-induced itch in human, revealing an interesting interspecies difference in TGR5 expression and function between mice and human.
This study, complimenting two recently published articles4,5, demonstrates that the bile acid receptor MRGPRX4 is an important receptor for mediating human cholestatic itch, providing a potential drug target for anti-itch therapies.
Original link: https://doi.org/10.7554/eLife.48431
1. Beuers, U., Kremer, A. E., Bolier, R. & Elferink, R. P. Pruritus in cholestasis: facts and fiction. Hepatology 60, 399-407, doi:10.1002/hep.26909 (2014).
2. Alemi, F. et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 123, 1513-1530, doi:10.1172/JCI64551 (2013).
3. Lieu, T. et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 147, 1417-1428, doi:10.1053/j.gastro.2014.08.042 (2014).
4. Meixiong, J. et al. Identification of a bilirubin receptor that may mediate a component of cholestatic itch. Elife 8, doi:10.7554/eLife.44116 (2019).
5. Meixiong, J., Vasavda, C., Snyder, S. H. & Dong, X. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus. Proc Natl Acad Sci U S A 116, 10525-10530, doi:10.1073/pnas.1903316116 (2019).