Novel Insights on MRGPRX2-Mediated Hypersensitivity to Neuromuscular Blocking Agents And Fluoroquinolones.

Jessy Elst,Marie-Line M Van Der Poorten,Margaretha A Faber,Michel Van Houdt,Eva Lion,Leander P De Puysseleyr,Christel Mertens,Viggo F Van Tendeloo,Athina L Van Gasse,Margo M Hagendorens,Vito Sabato,Chris H Bridts,Diana Campillo-Davo,Didier G Ebo,Marcus Maurer

doi:10.3389/fimmu.2021.668962

Abstract

Neuromuscular blocking agents (NMBAs) like atracurium and rocuronium as well as fluoroquinolones (FQs) cause mast cell-mediated anaphylaxis by activating Mas-related G protein-coupled receptor X2 (MRGPRX2), but many questions remain unanswered. Here, we address three of them, namely whether primary human mast cells show similar activation by these drugs as murine mast cells and mast cell lines, how sugammadex protects from atracurium-induced MRGPRX2-mediated mast cell activation, and why some but not all patients treated with rocuronium develop anaphylaxis. We used peripheral blood-derived cultured mast cells from healthy donors and patients, assessed mast cell activation and degranulation by quantifying intracellular calcium and CD63 expression, respectively, and made use of MRGPRX2-silencing, via electroporation with Dicer-substrate small interfering RNAs, and single cell flow cytometric analyses. Atracurium, ciprofloxacin, and levofloxacin activated and degranulated primary human mast cells, but only MRGPRX2-positive and not MRGPRX2-negative or -silenced mast cells. Sugammadex attenuated the atracurium-induced and MRGPRX2-mediated activation and degranulation of human mast cells by reducing free atracurium levels. The mast cells of patients with IgE-independent anaphylaxis to rocuronium were similar, in their MRGPRX2 expression and function, to those of patients with IgE-mediated anaphylaxis. These findings further improve our understanding of the role and relevance of MRGPRX2-driven mast cell activation in anaphylactic reactions to NMBAs and FQs and may help to improve their prediction, prevention, and treatment.

Highlights

The activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells (MCs) is held to be a major pathway in the pathogenesis of Immunoglobulin E (IgE)-independent immediate drug hypersensitivity reactions (IDHRs) that occur in response to neuromuscular blocking agents (NMBAs) such as atracurium and rocuronium as well as fluoroquinolones (FQs) such as moxifloxacin and ciprofloxacin
Many questions on the role of MRGPRX2 in Neuromuscular blocking agents (NMBAs)- and FQ-induced anaphylaxis remain unanswered and need to be addressed. These include, but are not limited to, 1) whether findings on MRGPRX2 activation by NMBAs and FQs from mouse models or genetically modified cell lines can be extrapolated to humans, 2) what the precise role and mechanisms of action of sugammadex, a NMBA reversal agent, are in atracurium-induced and MRGPRX2-induced adverse reactions [8], and 3) why some but not all patients treated with NMBAs experience MRGPRX2-related IDHRs
We show 1) that atracurium, ciprofloxacin and levofloxacin degranulate human MCs via MRGPRX2, 2) that sugammadex attenuates atracurium-induced and MRGPRX2mediated MC degranulation by reducing free atracurium, and 3) that rocuronium-hypersensitive patients with and without sensitization to this NMBA show similar mast cell MRGPRX2 expression and function

Summary

Introduction

The activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells (MCs) is held to be a major pathway in the pathogenesis of IgE-independent immediate drug hypersensitivity reactions (IDHRs) that occur in response to neuromuscular blocking agents (NMBAs) such as atracurium and rocuronium as well as fluoroquinolones (FQs) such as moxifloxacin and ciprofloxacin. Many questions on the role of MRGPRX2 in NMBA- and FQ-induced anaphylaxis remain unanswered and need to be addressed These include, but are not limited to, 1) whether findings on MRGPRX2 activation by NMBAs and FQs from mouse models or genetically modified cell lines can be extrapolated to humans, 2) what the precise role and mechanisms of action of sugammadex, a NMBA reversal agent, are in atracurium-induced and MRGPRX2-induced adverse reactions [8], and 3) why some but not all patients treated with NMBAs experience MRGPRX2-related IDHRs. At present, most of the information on the effects of NMBAs and FQs on MRGPRX2 are derived from studies performed with MRGPRX2-expressing neoplastic cells, like the LAD-2 MC line, or with the mouse orthologue, MRGPRB2. Until very recently, were not possible due to the lack of suitable tools, models and assays

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Conclusion