Roles of Mas-related G protein–coupled receptor X2 on mast cell–mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases

• Published in: Journal of allergy and clinical immunology Vol. 138; no. 3; pp. 700 - 710
• Main Authors: Subramanian, Hariharan, Gupta, Kshitij, Ali, Hydar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016; Elsevier Limited
• Subjects: Allergy and Immunology; Anaphylaxis - immunology; Animals; Antimicrobial agents; Asthma; Chronic Disease; chronic urticaria; Defense; Drug Hypersensitivity - immunology; drug-induced pseudoallergy; G protein–coupled receptor; Gene expression; host defense peptides; Human subjects; Humans; Immunity, Cellular; Infections; Inflammation - immunology; Inflammatory diseases; Ligands; mast cells; Mast Cells - immunology; MRGPRX2; Nerve Tissue Proteins - immunology; Neuropeptides; Pain - immunology; Pathogenesis; Peptides; Proteins; Receptors, G-Protein-Coupled - immunology; Receptors, Neuropeptide - immunology; Rodents; Signal transduction; PGD2; GRK; EPO; MCDP; neuropeptides; mast cells; MRGPRX2 (MrgX2); HDP; MC; CTMC; EC50; MBP; NK1R; SP; MCTC; MMC; MRGPRX2; PMC; chronic urticaria; asthma; hBD; MAPK; ORAI; SCA; drug-induced pseudoallergy; CU; host defense peptides; PTx; Mrgpr; DRG; GPCR; G protein–coupled receptor; VIP; CGRP; C3aR; MCT; Calcitonin gene–related peptide; Ca 2+ release–activated Ca 2+ channel; Human β-defensin; G protein–coupled receptor kinase; Mas-related G protein–coupled receptor X2; Peritoneal mast cell; Dorsal root ganglia; Substance P; Mas-related G protein–coupled receptor; Anaphylatoxin C3a receptor; EC 50; Vasoactive intestinal peptide; Mast cell; Tryptase and chymase-expressing mast cells; Prostaglandin D 2; Eosinophil peroxidase; Sickle cell anemia; Major basic protein; Mast cell degranulating peptide; Pertussis toxin; Mucosal mast cell; Concentration required to produce a 50% response; Neurokinin 1 receptor; Connective tissue mast cell; Tryptase-expressing mast cells; MC TC; Host defense peptide; Mitogen-activated protein kinase; MC T; PGD 2
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.04.051

Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, contribute to vascular homeostasis, innate/adaptive immunity, and wound healing. However, MCs are best known for their roles in allergic and inflammatory diseases, such as anaphylaxis, food allergy, rhinitis, itch, urticaria, atopic dermatitis, and asthma. In addition to the high-affinity IgE receptor (FcεRI), MCs express numerous G protein–coupled receptors (GPCRs), which are the largest group of membrane receptor proteins and the most common targets of drug therapy. Antimicrobial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and many US Food and Drug Administration–approved peptidergic drugs activate human MCs through a novel GPCR known as Mas-related G protein–coupled receptor X2 (MRGPRX2; formerly known as MrgX2). Unique features of MRGPRX2 that distinguish it from other GPCRs include their presence both on the plasma membrane and intracellular sites and their selective expression in MCs. In this article we review the possible roles of MRGPRX2 on host defense, drug-induced anaphylactoid reactions, neurogenic inflammation, pain, itch, and chronic inflammatory diseases, such as urticaria and asthma. We propose that host defense peptides that kill microbes directly and activate MCs through MRGPRX2 could serve as novel GPCR targets to modulate host defense against microbial infection. Furthermore, mAbs or small-molecule inhibitors of MRGPRX2 could be developed for the treatment of MC-dependent allergic and inflammatory disorders.