Cisatracurium induces mast cell activation and pseudo-allergic reactions via MRGPRX2

Abstract The prevalence of allergies has increased over the last four decades. In allergic reactions, mast cells induce a hypersensitive immune response to a substance that is normally harmless. Ionizing radiation has different biological effects depending on the dose and dose rate. In this study, we investigated whether low-dose irradiation before (preventative effect) or after (therapeutic effect) an antigen-antibody reaction has an anti-allergic effect. To test this, we activated rat basophilic leukemia (RBL-2H3) mast cells with anti-2,4-dinitrophenyl IgE (antibody) and 2,4-dinitrophenyl human serum albumin, which served as an antigen. To test for both the potential of a preventative effect and a therapeutic effect, we irradiated mast cells both before and after mast cell activation, and we measured mediator release and signaling pathway activity. Low-dose ionizing radiation suppressed mediator release from RBL-2H3 mast cells activated by the antigen-antibody reaction regardless of when the mast cells were irradiated. These results were due to the suppression of FcεRI expression. Therefore, we suggest that low-dose ionizing radiation has a preventative and therapeutic effect in allergic reactions via the FcεRI-mediated RBL-2H3 mast cell activation system.

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Ethanol Extract of Sesamum indicum Linn. Inhibits FcεRI-Mediated Allergic Reaction via Regulation of Lyn/Syk and Fyn Signaling Pathways in Rat Basophilic Leukemic RBL-2H3 Mast Cells

Mediators of Inflammation ◽

10.1155/2019/5914396 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Hyun Ju Do ◽

Tae Woo Oh ◽

Kwang-Il Park

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Signaling Pathways ◽

Inflammatory Mediators ◽

Cell Activation ◽

Immunoglobulin E ◽

Sesamum Indicum ◽

Mast Cell Activation ◽

Allergic Reactions ◽

Potent Effect

This study is aimed at determining whether Sesamum indicum Linn. beneficially influences FcεRI-mediated allergic reactions in RBL-2H3 mast cells; it is also aimed at further investigating Lyn/Fyn and Syk signaling pathways. To examine the antiallergic effect of Sesamum indicum Linn. extract (SIE), we treated antigen/immunoglobulin E- (IgE-) sensitized mast cells with extracts of various concentrations. We examined the degranulation release and concentrations of inflammatory mediators. Additionally, the expressions of genes involved in the FcεRI and arachidonate signaling pathways were examined. SIE inhibited the degranulation and secretion of inflammatory mediators in antigen/IgE-sensitized mast cells. SIE reduced the expressions of FcεRI signaling-related genes, such as Syk, Lyn, and Fyn, and the phosphorylation of extracellular signal-regulated kinase in antigen/IgE-sensitized mast cells. Additionally, in late allergic responses, SIE reduced PGD2 release and COX-2 and cPLA2 phosphorylation expression in FcεRI-mediated mast cell activation. Lastly, 250–500 mg/kg SIE significantly attenuated the Ag/IgE-induced passive cutaneous anaphylaxis (PCA) reaction in mice. The potent effect of SIE on RBL-2H3 mast cell activation indicates that the extract could potentially be used as a novel inhibitor against allergic reactions.

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Tespa1 negatively regulates FcεRI-mediated signaling and the mast cell–mediated allergic response

Journal of Experimental Medicine ◽

10.1084/jem.20140470 ◽

2014 ◽

Vol 211 (13) ◽

pp. 2635-2649 ◽

Cited By ~ 6

Author(s):

Di Wang ◽

Mingzhu Zheng ◽

Yuanjun Qiu ◽

Chuansheng Guo ◽

Jian Ji ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Cytokine Production ◽

Adaptor Protein ◽

Mast Cell Activation ◽

Allergic Reactions ◽

Proinflammatory Cytokine Production ◽

Increased Sensitivity ◽

Ige Mediated

Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in their degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. We show that the activation of mast cells is negatively regulated by the newly identified adaptor protein Tespa1. Loss of Tespa1 in mouse mast cells led to hyper-responsiveness to stimulation via FcεRI. Mice lacking Tespa1 also displayed increased sensitivity to IgE-mediated allergic responses. The dysregulated signaling in KO mast cells was associated with increased activation of Grb2-PLC-γ1-SLP-76 signaling within the LAT1 (linker for activation of T cells family, member 1) signalosome versus the LAT2 signalosome. Collectively, these findings show that Tespa1 orchestrates mast cell activation by tuning the balance of LAT1 and LAT2 signalosome assembly.

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Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor alpha chain respond to human IgE in mast cell degranulation and in allergic reactions.

Journal of Experimental Medicine ◽

10.1084/jem.183.1.49 ◽

1996 ◽

Vol 183 (1) ◽

pp. 49-56 ◽

Cited By ~ 49

Author(s):

W P Fung-Leung ◽

J De Sousa-Hitzler ◽

A Ishaque ◽

L Zhou ◽

J Pang ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Transgenic Mice ◽

Cell Activation ◽

Surface Expression ◽

Mast Cell Activation ◽

Cell Surface Expression ◽

Allergic Reactions ◽

Alpha Chain ◽

Ige Mediated

The high-affinity receptor for immunoglobulin (Ig) E (Fc epsilon RI) on mast cells and basophils plays a key role in IgE-mediated allergies. Fc epsilon RI is composed of one alpha, one beta, and two gamma chains, which are all required for cell surface expression of Fc epsilon RI, but only the alpha chain is involved in the binding to IgE. Fc epsilon RI-IgE interaction is highly species specific, and rodent Fc epsilon RI does not bind human IgE. To obtain a "humanized" animal model that responds to human IgE in allergic reactions, transgenic mice expressing the human Fc epsilon RI alpha chain were generated. The human Fc epsilon RI alpha chain gene with a 1.3-kb promoter region as a transgene was found to be sufficient for mast cell-specific transcription. Cell surface expression of the human Fc epsilon RI alpha chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in flow cytometric analyses. Expression of the transgenic Fc epsilon RI on bone marrow-derived mast cells was 4.7 x 10(4)/cell, and the human IgE-binding affinity was Kd = 6.4 nM in receptor-binding studies using 125I-IgE. The transgenic human Fc epsilon RI alpha chain was complexed with the mouse beta and gamma chains in immunoprecipitation studies. Cross-linking of the transgenic Fc epsilon RI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the Fc epsilon RI beta and gamma chains and other cellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by beta-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo. The results demonstrate that the human Fc epsilon RI alpha chain alone not only confers the specificity in human IgE binding, but also can reconstitute a functional receptor by coupling with the mouse beta and gamma chains to trigger mast cell activation and degranulation in a whole animal system. These transgenic mice "humanized" in IgE-mediated allergies may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.

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Mivacurium induce mast cell activation and pseudo-allergic reactions via MAS-related G protein coupled receptor-X2

Cellular Immunology ◽

10.1016/j.cellimm.2018.08.005 ◽

2018 ◽

Vol 332 ◽

pp. 121-128 ◽

Cited By ~ 7

Author(s):

Delu Che ◽

Jue Wang ◽

Yuanyuan Ding ◽

Rui Liu ◽

Jiao Cao ◽

...

Keyword(s):

Mast Cell ◽

G Protein ◽

Cell Activation ◽

Mast Cell Activation ◽

Allergic Reactions ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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

Cells ◽

10.3390/cells10051033 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1033

Author(s):

Mukesh Kumar ◽

Karthi Duraisamy ◽

Billy Kwok Chong CHOW

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Allergic Reaction ◽

G Protein ◽

Cell Activation ◽

Mast Cell Activation ◽

Allergic Reactions ◽

Ige Mediated ◽

G Protein Coupled

Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.

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