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

Ogasawara, Hiroyuki; Furuno, Masahiro; Edamura, Koji; Noguchi, Masato

doi:10.1002/jlb.2ab1018-405r

Cited by 48 publications

(31 citation statements)

References 39 publications

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“…Therefore, antagonizing MRGPRX2 is a rational therapeutic strategy for the prevention and treatment of anaphylactoid reactions. In recent years, several attempts have been made to target MRGPRX2 for screening antiallergic and anti-anaphylactoid molecules [36][37][38]. Recently some natural compounds such as quercetin [38], saikosaponin A [36], and shikonin [39] have been reported to inhibit mast cell degranulation and inhibit MRGPRX2-induced pseudo allergic reactions.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

et al. 2020

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Anaphylactoid shock is a fatal hypersensitivity response caused by non-IgE mediated mast cell activation. These reactions are mediated by a family of G protein-coupled receptors (GPCRs) known as Mas related GPCRX2 (MRGPRX2). Several US FDA approved drugs which are used in day to day life have been reported to cause anaphylactoid shock. Surprisingly, no therapeutic drugs are available which can directly target MRGPRX2 for treatment of anaphylactoid shock. Genistein is a non-steroidal polyphenol known for its diverse physiological and pharmacological activities. In recent studies, Genistein has been reported for its anti-inflammatory activity on mast cells. However, the effects and mechanistic pathways of Genistein on anaphylactoid reaction remain unknown. In the present study, we designed a battery of in-vitro, in-silico and in-vivo experiments to evaluate the anti-anaphylactoid activity of Genistein in order to understand the possible molecular mechanisms of its action. The in-vitro results demonstrated the inhibitory activity of Genistein on MRGPRX2 activation. Further, a mouse model of anaphylactoid shock was used to evaluate the inhibitory activity of Genistein on blood vessel leakage and hind paw edema. Taken together, our findings have demonstrated a therapeutic potential of Genistein as a lead compound in the treatment of anaphylactoid shock via MRGPRX2.

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Section: Discussionmentioning

confidence: 99%

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

et al. 2020

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“…As such, saikoside A, isoliquiritigenin, and PF could all inhibit MRGPRX2‐mediated MCs degranulation and pseudo‐allergic reactions. This may be explained by the fact that the MRGPRX2 receptor may act as a promiscuous receptor with respect to ligands (Ogasawara, Furuno, Edamura, & Noguchi, ), with agonists and antagonists having different binding sites on MRGPRX2.…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin inhibits MRGPRX2‐mediated pseudo‐allergic reaction via calcium signaling pathway

Wang

Zhang

Wang

et al. 2019

Phytotherapy Research

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Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) has been shown to be a pivotal target for pseudo-allergic diseases. Therefore, MRGPRX2 might be a therapeutic target for allergic contact dermatitis, atopic dermatitis, and red man syndrome. Paeoniflorin (PF) was reported to have an antiinflammatory effect in neuroinflammation, enteritis, and so forth. In this study, we investigated the anti-pseudo-allergic effect of PF and the underlying molecular mechanisms. Our results showed that PF can suppress compound 48/80 (C48/80)-induced PCA and MCs degranulation in vivo, in a dose-dependent manner. Moreover, PF can reduce C48/80-induced calcium influx and suppress MC degranulation and chemokines release in vitro. PF can downregulate the phosphorylation levels of key kinases in PLCγ-regulated calcium influx and subsequent cytokine synthesis pathways. Our study revealed that PF could inhibit C48/80-induced allergic responses both in vivo and in vitro. As such, it may be regarded as a novel inhibitor for preventing MRGPRX2mediated allergic diseases.

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“…Such a receptor is not only capable of initiating an inflammatory response without the adaptive immune system, but its ability to mediate MC-neuronal interactions and its relatively exclusive MC expression makes it an attractive target for MC-directed immunotherapeutics. Specific antagonism of the MRGPRX2 receptor is sufficient in inhibiting IgE-independent degranulation and could be used to lessen some drug-induced allergic reactions [21].…”

Section: Alternative Activation Paradigmsmentioning

confidence: 99%

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

Lyons

Pullen

2020

IJMS

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Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation—a pathway that is independent of the adaptive immune system—researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells’ ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.

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

Cited by 48 publications

References 39 publications

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

Paeoniflorin inhibits MRGPRX2‐mediated pseudo‐allergic reaction via calcium signaling pathway

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

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