A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice

被引：40

作者：

Wolf, Katharina ^{[1
,2
]}

Kuehn, Helen ^{[1
,2
]}

Boehm, Felicitas ^{[1
,2
]}

Gebhardt, Lisa ^{[1
,2
]}

Glaudo, Markus ^{[1
,2
]}

Agelopoulos, Konstantin ^{[3
]}

Staender, Sonja ^{[3
]}

Ectors, Philipp ^{[4
]}

Zahn, Dirk ^{[4
]}

Riedel, Yvonne K. ^{[5
]}

Thimm, Dominik ^{[5
]}

Mueller, Christa E. ^{[5
]}

Kretschmann, Sascha ^{[6
]}

Kremer, Anita N. ^{[6
]}

Chien, Daphne ^{[7
]}

Limjunyawong, Nathachit ^{[7
]}

Peng, Qi ^{[7
]}

Dong, Xinzhong ^{[7
]}

Kolkhir, Pavel ^{[8
,9
,10
,11
,12
]}

Scheffel, Joerg ^{[9
,10
,11
,12
]}

Sogaard, Mia Lykke ^{[1
,2
]}

Weigmann, Benno ^{[1
,2
]}

Neurath, Markus F. ^{[1
,2
,13
]}

Hawro, Tomasz ^{[9
,10
,11
,12
]}

Metz, Martin ^{[9
,10
,11
,12
]}

Fischer, Michael J. M. ^{[14
]}

Kremer, Andreas E. ^{[1
,2
]}

机构：

[1] Univ Hosp Erlangen, Dept Med 1, Ulmenweg 18, D-91054 Erlangen, Germany

[2] Friedrich Alexander Univ Erlangen Nurnberg, Erlangen, Germany

[3] Univ Munster, Ctr Chron Pruritus, Dept Dermatol, Munster, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Comp Chem Ctr, Erlangen, Germany

[5] Univ Bonn, PharmaCtr Bonn, Pharmaceut Inst, Pharmaceut & Med Chem, Bonn, Germany

[6] Friedrich Alexander Univ Erlangen Nurnberg, Dept Med 5, Erlangen, Germany

[7] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA

[8] IM Sechenov First Moscow State Med Univ, Sechenov Univ, Div Immune Mediated Skin Dis, Moscow, Russia

[9] Charite Univ Med Berlin, Dermatol Allergol, Allergie Ctr Charite, Dept Dermatol & Allergol, Berlin, Germany

[10] Free Univ Berlin, Berlin, Germany

[11] Humboldt Univ, Berlin, Germany

[12] Berlin Inst Hlth, Berlin, Germany

[13] Deutsch Zentrum Immuntherapie DZI, German Ctr Immunotherapy, Erlangen, Germany

[14] Univ Vienna, Ctr Physiol & Pharmacol, Vienna, Austria

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2021年 / 148卷 / 02期

关键词：

Mas gene-related G protein-coupled receptors;   mast cells; pseudoallergic drug reactions; (drug-induced) pruritus; PROTEIN-COUPLED RECEPTORS; MAST-CELL; INDUCED PRURITUS; SUBSTANCE-P; HISTAMINE; HYPERSENSITIVITY; PAROXETINE; ITCH; ANTIHISTAMINES; MRGX2;

D O I：

10.1016/j.jaci.2020.12.655

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background: Mas gene-related G protein-coupled receptors (MRGPRs) are a G protein-coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgEindependent signaling and pseudoallergic drug reactions. Objectives: Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus. Methods: To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human. Results: We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans. Conclusion: Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions. (J Allergy Clin Immunol 2021;148:506-22.)

引用

页码：506 / +

页数：25

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