Abstract
Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.
Highlights
Mast cells (MCs) serve as sentinel innate immune cells, which store dense secretory granules containing mediators such as histamine, tumor necrosis factor α (TNF-α), serotonin, and a wide range of MC-specific serine proteases bound to a proteoglycan core containing heparin and glycosaminoglycans, and are responsible for host resistance to bacteria, multicellular parasites, and xenobiotic toxins [4]
mas-related GPCR-X2 (MRGPRX2), a very unique GPCR without parallel, and secondly discuss how MRGPRX2 activation may contribute to the etiology of neurogenic inflammation and pain, type 2 inflammatory reactions such as atopic dermatitis (AD), chronic urticaria (CU), allergic contact dermatitis (ACD), non-histaminergic itch, and small molecule compound-induced pseudoallergy
MRGPRX2 has been reported to be activated by major basic protein (MBP) and the tryptase fragment of MBP [18,32]. These results suggest that MRGPRX2-mediated MC activation by the activated eosinophils infiltrating into the skin lesions may be involved in further exacerbation of allergic skin diseases
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mast cells (MCs) are at the forefront of exposure to environmental factors and are known to be important players and regulators of innate immune responses to pathogens [1,2]. MC activation by basic secretagogues is mediated by the pertussis toxin (PTX)-sensitive G-proteins Gi2 and Gi3, which are known to be involved in phagocytosis. We will firstly outline the characteristics and downstream signaling of MRGPRX2, a very unique GPCR without parallel, and secondly discuss how MRGPRX2 activation may contribute to the etiology of neurogenic inflammation and pain, type 2 inflammatory reactions such as atopic dermatitis (AD), chronic urticaria (CU), allergic contact dermatitis (ACD), non-histaminergic itch, and small molecule compound-induced pseudoallergy. We propose that inhibiting the inappropriate activation of MRGPRX2 in MCs may lead to new therapeutic approaches for many allergic and inflammatory diseases
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