Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells.
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 D2 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.
['Ogasawara|Hiroyuki|H|0000-0003-2193-4868', 'Furuno|Masahiro|M|', 'Edamura|Koji|K|', 'Noguchi|Masato|M|0000-0002-3092-0946']
D001920:Bradykinin D000001:Calcimycin D005312:Fetal Blood D006801:Humans D007073:Immunoglobulin E D008407:Mast Cells D019950:Mitogen-Activated Protein Kinase 1 D048052:Mitogen-Activated Protein Kinase 3 D009419:Nerve Tissue Proteins D043562:Receptors, G-Protein-Coupled D018013:Receptors, Neuropeptide
degranulation basic secretagogue GPCR MAPK PGD2 inflammation pseudo-allergy