RSS-Feed abonnieren
DOI: 10.1055/s-0041-1730923
MRGPRX4 in Cholestatic Pruritus
Funding W.L. reports grants from NIH, during the conduct of the study.Abstract
Pruritus (itch) is a debilitating symptom in liver diseases with cholestasis, which severely affects patients' quality of life. Limited treatment options are available for cholestatic itch, largely due to the incomplete understanding of the underlying molecular mechanisms. Several factors have been proposed as pruritogens for cholestatic itch, such as bile acids, bilirubin, lysophosphatidic acid, and endogenous opioids. Recently, two research groups independently identified Mas-related G protein-coupled receptor X4 (MRGPRX4) as a receptor for bile acids and bilirubin and demonstrated its likely role in cholestatic itch. This discovery not only opens new avenues for understanding the molecular mechanisms in cholestatic itch but provides a promising target for developing novel anti-itch treatments. In this review, we summarize the current theories and knowledge of cholestatic itch, emphasizing MRGPRX4 as a bile acid and bilirubin receptor mediating cholestatic itch in humans. We also discuss some future perspectives in cholestatic itch research.
Publikationsverlauf
Artikel online veröffentlicht:
23. Juni 2021
© 2021. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
Reference
- 1 Kremer AE, Oude Elferink RP, Beuers U. Pathophysiology and current management of pruritus in liver disease. Clin Res Hepatol Gastroenterol 2011; 35 (02) 89-97
- 2 Düll MM, Kremer AE. Management of chronic hepatic itch. Dermatol Clin 2018; 36 (03) 293-300
- 3 Jones D, Boudes PF, Swain MG. et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol 2017; 2 (10) 716-726
- 4 de Vries E, Bolier R, Goet J. et al; Netherlands Association for the Study of the Liver-Cholestasis Working Group. Fibrates for Itch (FITCH) in fibrosing cholangiopathies: a double-blind, randomized, placebo-controlled trial. Gastroenterology 2021; 160 (03) 734-743.e6
- 5 Al-Dury S, Wahlström A, Wahlin S. et al. Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. Sci Rep 2018; 8 (01) 6658
- 6 Hegade VS, Kendrick SF, Dobbins RL. et al. BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial. BMC Gastroenterol 2016; 16 (01) 71
- 7 Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339 (17) 1217-1227
- 8 Zollner G, Trauner M. Mechanisms of cholestasis. Clin Liver Dis 2008; 12 (01) 1-26 , vii
- 9 Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician 2004; 69 (02) 299-304
- 10 Roger D, Vaillant L, Fignon A. et al. Specific pruritic diseases of pregnancy. A prospective study of 3192 pregnant women. Arch Dermatol 1994; 130 (06) 734-739
- 11 Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006; 26 (09) 527-532
- 12 Szczęch J, Wiatrowski A, Hirnle L, Reich A. Prevalence and relevance of pruritus in pregnancy. BioMed Res Int 2017; 2017: 4238139
- 13 Beuers U, Kremer AE, Bolier R, Elferink RP. Pruritus in cholestasis: facts and fiction. Hepatology 2014; 60 (01) 399-407
- 14 Sanjel B, Shim W-S. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: a review. Biochim Biophys Acta Mol Basis Dis 2020; 1866 (12) 165958-165958
- 15 Alemi F, Kwon E, Poole DP. et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123 (04) 1513-1530
- 16 Lieu T, Jayaweera G, Zhao P. et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 2014; 147 (06) 1417-1428
- 17 Bergasa NV. Lysophosphatidic acid and atotaxin in patients with cholestasis and pruritus: fine biology, anticipated discernme. Ann Hepatol 2010; 9 (04) 475-479
- 18 Kremer AE, Martens JJ, Kulik W. et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139 (03) 1008-1018 , 1018.e1
- 19 Kittaka H, Uchida K, Fukuta N, Tominaga M. Lysophosphatidic acid-induced itch is mediated by signalling of LPA5 receptor, phospholipase D and TRPA1/TRPV1. J Physiol 2017; 595 (08) 2681-2698
- 20 Azimi E, Reddy VB, Pereira PJS, Talbot S, Woolf CJ, Lerner EA. Substance P activates MAS-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol 2017; 140 (02) 447-453.e3
- 21 Sanjel B, Maeng HJ, Shim WS. BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus. Sci Rep 2019; 9 (01) 10888
- 22 Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists: relevant after all these years. Med Hypotheses 2018; 110: 86-89
- 23 Nguyen E, Lim G, Ding H, Hachisuka J, Ko MC, Ross SE. Morphine acts on spinal dynorphin neurons to cause itch through disinhibition. Sci Transl Med 2021; 13 (579) eabc3774
- 24 Datta DV, Sherlock S. Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology 1966; 50 (03) 323-332
- 25 van de Peppel IP, Verkade HJ, Jonker JW. Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids. Am J Physiol Gastrointest Liver Physiol 2020; 319 (05) G619-G625
- 26 Slavetinsky C, Sturm E. Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis. BMJ Case Rep 2020; 13 (06) e234185
- 27 Beuers U, Gerken G, Pusl T. Biliary drainage transiently relieves intractable pruritus in primary biliary cirrhosis. Hepatology 2006; 44 (01) 280-281
- 28 Ghent CN, Bloomer JR, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and topruritus. Gastroenterology 1977; 73 (05) 1125-1130
- 29 Schoenfield LJ, Sjövall J, Perman E. Bile acids on the skin of patients with pruritic hepatobiliary disease. Nature 1967; 213: 93-94
- 30 Meixiong J, Vasavda C, Green D. et al. Identification of a bilirubin receptor that may mediate a component of cholestatic itch. eLife 2019; 8: 8
- 31 Meixiong J, Vasavda C, Snyder SH, 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 2019; 116 (21) 10525-10530
- 32 Yu H, Zhao T, Liu S. et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. eLife 2019; 8: 8
- 33 Bader M, Alenina N, Andrade-Navarro MA, Santos RA. MAS and its related G protein-coupled receptors, MRGPRs. Pharmacol Rev 2014; 66 (04) 1080-1105
- 34 Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 2001; 106 (05) 619-632
- 35 Lembo PMC, Grazzini E, Groblewski T. et al. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 2002; 5 (03) 201-209
- 36 Meixiong J, Anderson M, Limjunyawong N. et al. Activation of Mast-cell-expressed Mas-related G-protein-coupled receptors drives non-histaminergic itch. Immunity 2019; 50 (05) 1163-1171.e5
- 37 Liu Q, Tang Z, Surdenikova L. et al. Sensory neuron-specific GPCR MRGPRs are itch receptors mediating chloroquine-induced pruritus. Cell 2009; 139 (07) 1353-1365
- 38 Liu Q, Sikand P, Ma C. et al. Mechanisms of itch evoked by β-alanine. J Neurosci 2012; 32 (42) 14532-14537
- 39 Inoue A, Ishiguro J, Kitamura H. et al. TGFα shedding assay: an accurate and versatile method for detecting GPCR activation. Nat Methods 2012; 9 (10) 1021-1029
- 40 Zhang R, Xie X. Tools for GPCR drug discovery. Acta Pharmacol Sin 2012; 33 (03) 372-384
- 41 Kroeze WK, Sassano MF, Huang XP. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol 2015; 22 (05) 362-369
- 42 Eliakim M, Eisner M, Ungar H. Experimental intrahepatic obstructive jaundice following ingestion of alphanaphthyl-iso-thiocyanate. Bull Res Counc Isr, Sect E; Exp Med 1959; 8E: 7-17
- 43 Laupacis A, Keown PA, Ulan RA, Sinclair NR, Stiller CR. Hyperbilirubinaemia and cyclosporin A levels. Lancet 1981; 2 (8260-61): 1426-1427
- 44 Kutty RK, Maines MD. Purification and characterization of biliverdin reductase from rat liver. J Biol Chem 1981; 256 (08) 3956-3962
- 45 Hagiwara D, Miyake H, Morimoto H, Murai M, Fujii T, Matsuo M. Studies on neurokinin antagonists. 1. The design of novel tripeptides possessing the glutaminyl-D-tryptophylphenylalanine sequence as substance P antagonists. J Med Chem 1992; 35 (11) 2015-2025
- 46 Azimi E, Reddy VB, Shade KC. et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight 2016; 1 (16) e89362
- 47 Cipriani S, Renga B, D'Amore C. et al. Impaired itching perception in murine models of cholestasis is supported by dysregulation of GPBAR1 signaling. PLoS One 2015; 10 (07) e0129866
- 48 Hodge RJ, Lin J, Vasist Johnson LS, Gould EP, Bowers GD, Nunez DJ. SB-756050 Project Team. Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in type 2 diabetes. Clin Pharmacol Drug Dev 2013; 2 (03) 213-222
- 49 Shim WS, Tak MH, Lee MH. et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007; 27 (09) 2331-2337
- 50 Wilson SR, Gerhold KA, Bifolck-Fisher A. et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011; 14 (05) 595-602
- 51 Freedman MR, Holzbach RT, Ferguson DR. Pruritus in cholestasis: no direct causative role for bile acid retention. Am J Med 1981; 70 (05) 1011-1016
- 52 Karczewski KJ, Francioli LC, Tiao G. et al; Genome Aggregation Database Consortium. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581 (7809): 434-443
- 53 Greim H, Trülzsch D, Czygan P. et al. Mechanism of cholestasis. 6. Bile acids in human livers with or without biliary obstruction. Gastroenterology 1972; 63 (05) 846-850
- 54 Chiang JY. Bile acid metabolism and signaling. Compr Physiol 2013; 3 (03) 1191-1212
- 55 Tian Y, Gui W, Koo I. et al. The microbiome modulating activity of bile acids. Gut Microbes 2020; 11 (04) 979-996
- 56 Kang DJ, Hylemon PB, Gillevet PM. et al. Gut microbial composition can differentially regulate bile acid synthesis in humanized mice. Hepatol Commun 2017; 1 (01) 61-70
- 57 Bajaj JS, Fagan A, Sikaroodi M. et al. Alterations in skin microbiomes of patients with cirrhosis. Clin Gastroenterol Hepatol 2019; 17 (12) 2581-2591.e15
- 58 Studer N, Desharnais L, Beutler M. et al. Functional intestinal bile acid 7α-dehydroxylation by Clostridium scindens associated with protection from Clostridium difficile Infection in a Gnotobiotic Mouse Model. Front Cell Infect Microbiol 2016; 6: 191
- 59 Bassari R, Koea JB. Jaundice associated pruritis: a review of pathophysiology and treatment. World J Gastroenterol 2015; 21 (05) 1404-1413
- 60 Barcellini W, Fattizzo B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Dis Markers 2015; 2015: 635670
- 61 Dawson PA. Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 2011; (201) 169-203
- 62 Vaz FM, Paulusma CC, Huidekoper H. et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 2015; 61 (01) 260-267
- 63 Dong C, Zhang BP, Wang H. et al. Clinical and histopathologic features of sodium taurocholate cotransporting polypeptide deficiency in pediatric patients. Medicine (Baltimore) 2019; 98 (39) e17305
- 64 Heikkinen J, Mäentausta O, Ylöstalo P, Jänne O. Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br J Obstet Gynaecol 1981; 88 (03) 240-245
- 65 Schock H, Zeleniuch-Jacquotte A, Lundin E. et al. Hormone concentrations throughout uncomplicated pregnancies: a longitudinal study. BMC Pregnancy Childbirth 2016; 16 (01) 146
- 66 Lansu K, Karpiak J, Liu J. et al. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 2017; 13 (05) 529-536
- 67 Oeda S, Takahashi H, Yoshida H. et al; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Prevalence of pruritus in patients with chronic liver disease: a multicenter study. Hepatol Res 2018; 48 (03) E252-E262
- 68 Koulentaki M, Ioannidou D, Stefanidou M. et al. Dermatological manifestations in primary biliary cirrhosis patients: a case control study. Am J Gastroenterol 2006; 101 (03) 541-546
- 69 Rishe E, Azarm A, Bergasa NV. Itch in primary biliary cirrhosis: a patients' perspective. Acta Derm Venereol 2008; 88 (01) 34-37
- 70 Tanaka A, Miura K, Yagi M. et al. The assessment of subjective symptoms and patient-reported outcomes in patients with primary biliary cholangitis using PBC-40. Kanzo 2016; 57 (09) 457-467
- 71 Maticic M, Poljak M, Lunder T, Rener-Sitar K, Stojanovic L. Lichen planus and other cutaneous manifestations in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area. J Eur Acad Dermatol Venereol 2008; 22 (07) 779-788
- 72 Cribier B, Samain F, Vetter D, Heid E, Grosshans E. Systematic cutaneous examination in hepatitis C virus infected patients. Acta Derm Venereol 1998; 78 (05) 355-357
- 73 Cacoub P, Poynard T, Ghillani P. et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum 1999; 42 (10) 2204-2212
- 74 Reddy VB, Azimi E, Chu L, Lerner EA. Mas-related G-protein coupled receptors and Cowhage-induced itch. J Invest Dermatol 2018; 138 (02) 461-464
- 75 Han SK, Dong X, Hwang JI, Zylka MJ, Anderson DJ, Simon MI, Orphan G. protein-coupled receptors Mrga1 and Mrgc11 are distinctively activated by RF-amide-related peptides through the Gαq/11 pathway. Paper presented at: Proceedings of the National Academy of Sciences of the United States of America; 2002
- 76 Reddy VB, Sun S, Azimi E, Elmariah SB, Dong X, Lerner EA. Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of MRGPRs. Nat Commun 2015; 6: 7864
- 77 Liu Q, Weng HJ, Patel KN. et al. The distinct roles of two GPCRs, MRGPRC11 and PAR2, in itch and hyperalgesia. Sci Signal 2011; 4 (181) ra45
- 78 Azimi E, Reddy VB, Lerner EA. Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila) 2017; 2 (01) e5
- 79 Shinohara T, Harada M, Ogi K. et al. Identification of a G protein-coupled receptor specifically responsive to β-alanine. J Biol Chem 2004; 279 (22) 23559-23564
- 80 Yang Y, Sun Y, Guan D. et al. Allantoin induces pruritus by activating MRGPRD in chronic kidney disease. bioRxiv 2020; . Online ahead of print DOI: 10.1101/2020.10.26.354654.
- 81 Madeira F, Park YM, Lee J. et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 2019; 47 (W1): W636-W641
- 82 Rambaut A. FigTree: A Graphical Viewer of Phylogenetic Trees. 1.4.4 ed. Edinburgh: The author, Institute of Evolutionary Biology, University of Edinburgh