Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Kumar, Mukesh; Duraisamy, Karthi; Chow, Billy K. C.

doi:10.3390/cells10051033

Cited by 65 publications

(74 citation statements)

References 197 publications

(365 reference statements)

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“…Also, in an “immuno-active” group of IBS patients, genes coding for the pro-inflammatory cytokine IL-1β and mast cell G-protein coupled receptor MRGPRX2, as well as the cyclooxygenase gene PTGS2 were significantly upregulated in the colon compared to healthy controls ( Aguilera-Lizarraga et al, 2019 ). All of these have been implicated in mast cell activation ( Aguilera-Lizarraga et al, 2019 ), with MRGPRX2 in specific mediating IgE-independent mast cell activation in response to various ligands including eosinophil cationic proteins ( Ali, 2016 ; Kumar et al, 2021 ).…”

Section: Factors Related To Immune Activationmentioning

confidence: 99%

Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect

et al. 2022

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Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.

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Section: Factors Related To Immune Activationmentioning

confidence: 99%

Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect

et al. 2022

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“…Since 85% of the patients who had pseudoallergic reactions to neuromuscular blocking agents were not previously treated with neuromuscular blocking agents [ 127 ], IgE-independent MC activation by neuromuscular blocking agents may be a factor causing pseudoallergic reactions. It has been reported that the pseudo-allergic reactions to several FDA-approved drugs were from MRGPRX2-mediated MC activation [ 20 , 128 , 129 ]. Subsequently, clozapine, an antipsychotic drug, and codeine have been reported to cause pseudoallergic reactions via MRGPRX2 [ 54 , 130 ].…”

Section: Drug-induced Pseudoallergic Reactionmentioning

confidence: 99%

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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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.

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“…With the discovery of Mas-related G protein-coupled receptor member X2 (MRGPRX2) as a key receptor of IgE-independent mast cell (MC) degranulation, two similarly effective routes of degranulation are now established in skin MCs [1,2]. The presumed clinical significance of MRGPRX2 stems from the plethora of ligands, both endogenous and exogenous, that reportedly activate the receptor [1,[3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

Wang

Franke

Bal

et al. 2022

Cells

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The recent discovery of MRGPRX2 explains mast cell (MC)-dependent symptoms independently of FcεRI-activation. Because of its novelty, signaling cascades triggered by MRGPRX2 are rudimentarily understood, especially in cutaneous MCs, by which MRGPRX2 is chiefly expressed. Here, MCs purified from human skin were used following preculture or ex vivo and stimulated by FcεRI-aggregation or MRGPRX2 agonists (compound 48/80, Substance P) in the presence/absence of inhibitors. Degranulation was assessed by β-hexosaminidase or histamine release. Phosphorylation events were studied by immunoblotting. As a G protein-coupled receptor, MRGPRX2 signals by activating G proteins; however, their nature has remained controversial. In skin MCs, Gαi and Gαq were required for degranulation, but Gαi was clearly more relevant. Ca++ channels were likewise crucial. Downstream, PI3K was essential for granule discharge initiated by MRGPRX2 or FcεRI. ERK1/2 and JNK were additional participants, especially in the allergic route. Addressing possible points of intersection between early and later events, pERK1/2 and pAKT were found to depend on Gαi, further highlighting its significance. Gαq and Ca++ channels made some contributions to the phosphorylation of ERK. Ca++ differentially affected PI3K activation in FcεRI- vis-à-vis MRGPRX2-signaling, as channel inhibition increased pAKT only when triggered via FcεRI. Collectively, our study significantly extends our understanding of the molecular framework behind granule secretion from skin MCs.

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Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Cited by 65 publications

References 197 publications

Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect

Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

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