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Novel MRGPRX2 antagonists inhibit IgE‐independent activation of human umbilical cord blood‐derived mast cells
Author(s) -
Ogasawara Hiroyuki,
Furuno Masahiro,
Edamura Koji,
Noguchi Masato
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.2ab1018-405r
Subject(s) - degranulation , biology , immunoglobulin e , histamine , pharmacology , mast cell , receptor , immunology , antibody , biochemistry
Abstract Human MCs are primary effectors implicated in immune surveillance and defense by secreting histamine and various inflammatory mediators, a mechanism termed as degranulation. MCs can be activated by two pathways: IgE‐dependent classical pathway and the IgE‐independent pathway that utilizes various cationic molecules including substance P (SP) and pituitary adenylate cyclase‐activating polypeptides, which are host defense peptides collectively known as basic secretagogues. Our pharmacological study investigated whether or not IgE‐independent MC activation is mediated via MRGPRX2. We identified two novel MRGPRX2 antagonists, which completely inhibited the degranulation of human cord blood‐derived MCs (hCMCs) induced by basic secretagogues and pseudoallergic drug, icatibant, but IgE‐ or A23187‐challenged hCMCs were resistant to MRGPRX2 antagonists. The MRGPRX2 antagonists markedly inhibited the de novo synthesis of SP‐induced prostaglandin D 2 in hCMCs. Moreover, the antagonists were able to inhibit p42/44 mitogen‐activated protein kinase signal in hCMCs activated by SP. This study strongly suggests that MRGPRX2 antagonists may be a promising drug to prevent the IgE‐independent allergic reactions, and thus, MRGPRX2 antagonist development may lead to a promising therapeutic medication for the IgE‐independent allergic reactions.