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

Che, Delu; Liu, Rui; Cao, Jiao; Wang, Jue; Zhang, Yongjing; Ding, Yuanyuan; Zhao, Tingting; Ma, Pengyu; An, Hongli; Gao, Zijun; Zhang, Tao

doi:10.1016/j.intimp.2018.07.020

Cited by 40 publications

(23 citation statements)

References 21 publications

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“…Activation not only of mast cell but also of basophil and eosinophil MRGPRX2 might contribute to hypersensitivity reactions. Nevertheless, at the moment, most data indicating MRGPRX‐mediated anaphylactoid reactions are derived from mouse models or cell lines . Recently, human skin mast cell MRGPRX2 upregulation has been demonstrated in severe chronic spontaneous urticaria, a disease in which the role of specific IgE against allergens is negligible and against autoallergens debated .…”

Section: Discussionmentioning

confidence: 99%

The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function

Wedi

Gehring

Kapp

2020

Allergy

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Background Mas‐related G protein‐coupled receptor X2 (MRGPRX2) is regarded as a mast cell‐specific receptor mediating non–IgE‐dependent activation. We aimed to investigate whether human basophils and eosinophils express functional MRGPRX2. Methods Flow cytometry, immunocytochemistry, immunofluorescence, Western blot, and RT‐PCR were performed in highly purified peripheral blood basophils and eosinophils of atopic and nonatopic donors. To assess functional activity, fluorescent avidin‐based degranulation assay, calcium mobilization, cytokine production in supernatants, assessment of viability/apoptosis, and tricolor granulocyte activation test were used. Results MRGPRX2 was significantly expressed by basophils and eosinophils but not neutrophils. Functional capacity was shown by anti‐MRGPRX2 mAb‐induced calcium influx and concentration‐dependent induction of degranulation. Sequential stimulation in the calcium mobilization assay gave no evidence for desensitization or receptor internalization. Anti‐MRGPRX2 mAb significantly promoted survival. Inhibition of apoptosis could be due to released IL‐3, IL‐5, and GM‐CSF found in supernatants. Short‐term incubation with IL‐3 dose‐dependently upregulated MRGPRX2 expression in both, stimulation for 24 hours with anti‐IgE, C5a, fMLP, and IL‐3 in basophils and by IL‐3, IL‐5, and IL‐33 in eosinophils. Among known mast cell MRGPRX2 agonists ciprofloxacin but not PMX‐53 was functional on basophils and eosinophils. In basophils of allergic subjects, tricolor granulocyte activation test using grass pollen demonstrated MRGPRX2 upregulation associated with degranulation and CD63 expression. Conclusion Unraveling the regulation and signaling mechanisms of MRGPRX2 on basophils and eosinophils might enable the development of new therapeutic strategies to prevent or inhibit allergic and nonallergic hypersensitivity. Moreover, addressing MRGPRX2 might have potential for diagnostic purposes in (drug) hypersensitivity.

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Section: Discussionmentioning

confidence: 99%

The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function

Wedi

Gehring

Kapp

2020

Allergy

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“…Mast cell MRGPRX2 plays a pivotal role in mediating pseudo-allergic reactions to several FDA approved drugs (3,(19)(20)(21)(22)(23)(24) and chronic inflammation associated with asthma (18), urticaria (7), and rosacea (6). We have identified a role for SOCE via STIM1 in regulating MRGPRX2 responses in mast cells.…”

Section: Discussionmentioning

confidence: 96%

“…This receptor is activated by the same ligands as MRGPRX2 and displays considerable homology with the human receptor. Interestingly, several FDA approved drugs serve as ligands for MRGPRX2 (3,(19)(20)(21)(22)(23)(24) and consequently cause pseudo-allergic reactions in humans; however, the mechanism(s) utilized by this receptor to promote mast cell activation is not well-understood.…”

Section: Introductionmentioning

confidence: 99%

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

et al. 2020

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Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca 2+) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca 2+ levels; however, the Ca 2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca 2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.

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“…The NMBA atracurium and its isomer cisatracurium induce intracellular calcium influx and MC degranulation via MRGPRX2 in vitro. 26,98 Other NMBAs such as tubocurarine and mivacurium also likely activate MRGPRX2, as they have been shown to be agonists for the murine MRGPRX2 homolog Mrgprb2. 26 All 3 substances provoke wheal and flare responses following intradermal injection in humans.…”

Section: Drugs That Activate Mrgprx2mentioning

confidence: 99%

Mas-related G protein–coupled receptor X2 and its activators in dermatologic allergies

Kühn

Kolkhir

Babina

et al. 2021

Journal of Allergy and Clinical Immunology

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

Cited by 40 publications

References 21 publications

The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function

The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

Mas-related G protein–coupled receptor X2 and its activators in dermatologic allergies

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