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

Zhang

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.

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2019

Phytotherapy Research

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Journal of Dermatological Science

“…Male C57BL/6 mice, C57BL/6 STOCK Kit WÀsh/WÀsh mice and C57BL/6 MrgprB2-knockout mice were anesthetized with an intraperitoneal injection of 80 mg/kg 1% pelltobarbitalum natricum. Hind paw swelling and extravasation assay was performed as described previously [18]. Briefly, each mouse was injected intravenously (i.v.)…”

Section: Hind Paw Swelling and Extravasationmentioning

confidence: 99%

“…Varying (1.25, 2.5, 5 mg/ml) concentrations of thimerosal were added into corresponding well, 30 mg/ml Compound 48/80 was used as a positive control, and Tyrode's solution buffer only was a negative control. Beta-hexosaminidase release assay was performed as described previously [18].…”

Section: β-Hexosaminidase Assaymentioning

confidence: 99%

“…MRGPRX2 and MrgprB2 are expressed at high levels in mast cells in human and mouse skin, respectively [13,14]. Previous studies have shown that mouse MrgprB2 and the human MRGPRX2 are activated not only by basic secretagogues and neurokinins [17,18], but also a number of small-molecule drugs (such as antimicrobials, mivacurium) [18,19], producing direct mast cell degranulation and pseudo-allergic reactions. However, whether thimerosal can directly activate mast cells to induce contact dermatitis has not been reported.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thimerosal induces skin pseudo-allergic reaction via Mas-related G-protein coupled receptor B2

Peng

Che

Hao

et al. 2019

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Background: Thimerosal has been used as a preservative in many products which may cause contact dermatitis. It is the second most common allergen in positive patch test reactions, though being a clinical irrelevant allergen. Thimerosal-induced contact dermatitis is generally considered to be a delayed-type hypersensitivity reaction, but it is difficult to explain the fact that most patients develop an allergic reaction upon first encounter with thimerosal. Recent studies have demonstrated the association between Mas-related G protein coupled receptor X2 (MRGPRX2) and pseudo-allergic reactions which occur at the first contact with stimulation. This suggests the possibility that thimerosal may cause contact dermatitis via MRGPRX2 mediated mechanism. Objectives: To investigate the role of Mas-related G-protein coupled receptor B2 (MrgprB2)/MRGPRX2 in contact dermatitis induced by thimerosal. Methods: Thimerosal induced pseudo-allergic reactions via MrgprB2/ MRGPRX2 were investigated using a novel skin pseudo-allergic reaction mouse model, footpad swelling and extravasation assays in vivo and mast cell degranulation assay in vitro. Results: Thimerosal induced contact dermatitis in dorsal skin and footpad swelling in wild-type mice, but had no significant effect in MrgprB2-knockout mice. Thimerosal-induced dermatitis is characterized by infiltration of inflammatory cells and elevation of serum histamine and inflammatory cytokines, rather than elevation of serum IgE level. Thimerosal increased the intracellular Ca 2+ concentration in HEK293 cells overexpressing MrgprB2/MRGPRX2. Downregulation of MRGPRX2 resulted in the reduced degranulation of LAD2 human mast cells. Conclusions: MrgprB2 mediates thimerosal-induced mast cell degranulation and pseudo-allergic reaction in mice. MRGPRX2 may be a key contributor to human contact dermatitis.

“…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

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.