Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells.

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 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.

• Authors: Hiroyuki Ogasawara, Masahiro Furuno, Koji Edamura, Masato Noguchi
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 106 Issue 5 Pg. 1069-1077 (11 2019) ISSN: 1938-3673 [Electronic] England
• PMID: 31299111 (Publication Type: Journal Article)
• Copyright: ©2019 Society for Leukocyte Biology.

Chemical References

• MRGPRX2 protein, human
• Nerve Tissue Proteins
• Receptors, G-Protein-Coupled
• Receptors, Neuropeptide
• Immunoglobulin E
• Calcimycin
• icatibant
• MAPK1 protein, human
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Bradykinin

Topics

• Bradykinin (analogs & derivatives, pharmacology)
• Calcimycin (pharmacology)
• Fetal Blood (cytology, immunology)
• Humans
• Immunoglobulin E (immunology)
• Mast Cells (cytology, immunology)
• Mitogen-Activated Protein Kinase 1 (immunology)
• Mitogen-Activated Protein Kinase 3 (immunology)
• Nerve Tissue Proteins (antagonists & inhibitors, immunology)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, immunology)
• Receptors, Neuropeptide (antagonists & inhibitors, immunology)