Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

Benjamin D. McNeil, Priyanka Pundir, Sonya Meeker, Liang Han, Bradley J Undem, Marianna Kulka, Xinzhong Dong

Research output: Contribution to journalArticle

Abstract

Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

Original languageEnglish (US)
Pages (from-to)237-241
Number of pages5
JournalNature
Volume519
Issue number7542
DOIs
StatePublished - Mar 12 2015

Fingerprint

Mast Cells
Hypersensitivity
Pharmaceutical Preparations
Inflammation
Injections
Antibodies
Histamine Release
United States Food and Drug Administration
G-Protein-Coupled Receptors
Knockout Mice
Immunoglobulin E
Histamine
Peptides
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. / McNeil, Benjamin D.; Pundir, Priyanka; Meeker, Sonya; Han, Liang; Undem, Bradley J; Kulka, Marianna; Dong, Xinzhong.

In: Nature, Vol. 519, No. 7542, 12.03.2015, p. 237-241.

Research output: Contribution to journalArticle

McNeil, Benjamin D. ; Pundir, Priyanka ; Meeker, Sonya ; Han, Liang ; Undem, Bradley J ; Kulka, Marianna ; Dong, Xinzhong. / Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. In: Nature. 2015 ; Vol. 519, No. 7542. pp. 237-241.
@article{d129aa0895bf40a9a79f64631bd564ee,
title = "Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions",
abstract = "Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.",
author = "McNeil, {Benjamin D.} and Priyanka Pundir and Sonya Meeker and Liang Han and Undem, {Bradley J} and Marianna Kulka and Xinzhong Dong",
year = "2015",
month = "3",
day = "12",
doi = "10.1038/nature14022",
language = "English (US)",
volume = "519",
pages = "237--241",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7542",

}

TY - JOUR

T1 - Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

AU - McNeil, Benjamin D.

AU - Pundir, Priyanka

AU - Meeker, Sonya

AU - Han, Liang

AU - Undem, Bradley J

AU - Kulka, Marianna

AU - Dong, Xinzhong

PY - 2015/3/12

Y1 - 2015/3/12

N2 - Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

AB - Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

UR - http://www.scopus.com/inward/record.url?scp=84925521365&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925521365&partnerID=8YFLogxK

U2 - 10.1038/nature14022

DO - 10.1038/nature14022

M3 - Article

C2 - 25517090

AN - SCOPUS:84925521365

VL - 519

SP - 237

EP - 241

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7542

ER -