Abstract
Background
Hypersensitivity reactions, including anaphylaxis, can be triggered via the MRGPRX2 pathway and its murine ortholog, Mrgprb2. Acetylsalicylic acid (ASA) is known to exacerbate anaphylaxis due to the reduction of the homeostatic lipid mediator prostaglandin E2 (PGE2).Objectives
This study aimed to investigate the regulatory role of PGE2 in MRGPRX2/b2-mediated anaphylaxis and to determine how ASA may aggravate anaphylactic severity.Methods
A murine model of systemic Mrgprb2-mediated anaphylaxis was employed. Mice were treated with ASA, an inhibitor of the PGE2-degrading enzyme, and/or selective agonists targeting individual EP receptors. Mast cells were isolated from murine peritoneum and human skin, then exposed to PGE2, EP receptor agonists or antagonists, and subjected to RNA interference (RNAi) experiments. Epidemiological analyses were performed using data from the anaphylaxis registry.Results
Murine data provide evidence that endogenous PGE2 regulates ASA-potentiated, Mrgprb2-mediated anaphylaxis through EP3 and EP4 receptor signaling. Accordingly, exogenous PGE2 markedly attenuated MRGPRX2/b2-driven mast cell activation in vitro, predominantly via EP2 and EP3 receptors. These findings are supported by data from anaphylaxis registry indicating that the severity of anaphylaxis induced by drugs acting via MRGPRX2 is increased when NSAIDs are concomitantly taken.Conclusions
Our findings demonstrate the protective role of PGE2 through mitigating MRGPRX2/b2-mediated anaphylaxis via a direct reduction of mast cell activation. Further studies are needed to clarify whether EP receptors may serve as therapeutic targets for preventing or modifying anaphylactic responses.