MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia

Abstract

The study of anaphylactoid reactions during perioperative procedures and anaesthesia represents a diagnostic challenge for allergists, as many drugs are administered simultaneously, and approximately half of them trigger allergic reactions without a verifiable IgE-mediated mechanism. Recently, mast cell receptor MRGPRX2 has been identified as a cause of pseudo-allergic drug reactions. In this study, we analyse the ability of certain drugs used during perioperative procedures and anaesthesia to induce MRGPRX2-dependent degranulation in human mast cells and sera from patients who experienced an anaphylactoid reaction during the perioperative procedure. Using a β-hexosaminidase release assay, several drugs were seen to cause mast cell degranulation in vitro in comparison with unstimulated cells, but only morphine, vancomycin and cisatracurium specifically triggered this receptor, as assessed by the release of β-hexosaminidase in the control versus the MRGPRX2-silenced cells. The same outcome was seen when measuring degranulation based on the percentage of CD63 expression at identical doses. Unlike that of the healthy controls, the sera of patients who had experienced an anaphylactoid reaction induced mast-cell degranulation. The degranulation ability of these sera decreased when MRGPRX2 was silenced. In conclusion, MRGPRX2 is a candidate for consideration in non-IgE-mediated allergic reactions to some perioperative drugs, reinforcing its role in mast cell responses and their pathophysiology.

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

“…In a recent report in 2019 by IUPHAR/BPS, MRGPRX2 is listed as a Class A orphan GPCR for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to disease [17]. Now, it is known that direct activation of MRGPRX2 causes anaphylactoid shock in humans [1,18]. Unlike other GPCRs, MRGPRX2 can be activated by a plethora of chemicals including cationic amphiphilic drugs (tubocurarine, atracurium, icatibant, ciprofloxacin, and other fluoroquinolone antibiotics), insect venom chemical components (mastoparan and Polistes kinin), antimicrobial peptides (alpha-and beta-defensins and cathelicidins), secreted eosinophil products (eosinophil peroxidase and major basic protein), and neuropeptides (substance P, vasoactive intestinal peptide, neuropeptide Y, somatostatin, and cortistatin) [12,19].…”

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

“…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.…”

“…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.…”

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

“…The mechanism of pseudo-allergic reaction is not yet completely understood. Most of the time pseudo-allergic reaction is a candidate for consideration in IgE-independent allergic reactions [14,25], but given the symptoms of pseudo-allergy, the most likely explanation could be the hypothesis that certain antigens activate the effector cells of allergic inflammation, such as mast cells, without evidence of antigen-specific IgE, IgG or T cells [26]. Recent studies linked the pseudo-allergic reaction to a single receptor on mast cell, known as MRGPRX2 in human.…”