Anaphylaxis, drug allergy, urticaria, and angioedema
PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness

https://doi.org/10.1016/j.jaci.2020.03.046Get rights and content

Background

Reduced levels of prostaglandin E2 (PGE2) contribute to aspirin-induced hypersensitivity. COX inhibitors are also frequent cofactors in anaphylaxis. Whether alterations in the PGE2 system contribute to anaphylaxis independently of COX inhibitor intake is unclear.

Objective

Our aim was to test the hypothesis that relative PGE2 deficiency predisposes to anaphylaxis.

Methods

Sera from 48 patients with anaphylaxis and 27 healthy subjects were analyzed for PGE2 levels and correlated against severity; 9α,11β-PGF2 and PGI2 metabolites were measured for control purposes. PGE2 stabilization by 15-hydroxyprostaglandin dehydrogenase inhibitor or EP2 or EP4 receptor agonists were used in a murine model of passive systemic anaphylaxis. FcεRI-triggered mediator release was determined in bone marrow–derived cultured mast cells (MCs) and human skin–derived MCs. Signaling was studied by Western blot analysis.

Results

Patients with anaphylaxis were characterized by markedly reduced PGE2 levels vis-à-vis healthy subjects, whereas prostacyclin metabolite levels were diminished only weakly, and 9α,11β-PGF2 levels conversely increased. PGE2 was negatively correlated with severity. Lower PGE2 levels and higher susceptibility to anaphylaxis were also found in C57BL/6 mice vis-à-vis in Balb/c mice. Stabilization of PGE2 level by 15-hydroxyprostaglandin dehydrogenase inhibitor protected mice against anaphylaxis. Exogenous PGE2 attenuated bone marrow–derived cultured MC activation through EP2 and EP4 receptors. EP2 and EP4 agonism also curbed FcεRI-mediated degranulation of human MCs. Mechanistically, PGE2 interfered with the phosphorylation of phospholipase C gamma-1 and extracellular signal–regulated kinase.

Conclusions

Homeostatic levels of PGE2 attenuate MC activation via EP2/EP4 and protect against anaphylaxis. Relative deficiency of PGE2 predisposes to anaphylaxis in humans and mice, whereas PGE2 stabilization protects against anaphylactic reactions.

Section snippets

Anaphylaxis registry, data extraction, and analysis

The European Anaphylaxis Registry, which contains data from patients with anaphylactic reactions, has been covered by several publications.4,6,22 Serum samples from 48 patients with a history of Hymenoptera sting anaphylaxis were collected in 2010-2019. A group of 27 healthy subjects served as controls. Severity was classified according to anaphylaxis severity grade (Ring and Mesmer23), as based on the clinical reaction patterns of the most recent anaphylaxis episode (assessed before first aid

Patients with anaphylaxis are characterized by lower levels of PGE2

To test our hypothesis that low PGE2 level predisposes to severe allergic reactions, we analyzed sera from 48 patients with a history of Hymenoptera sting anaphylaxis for levels of PGE2 in comparison with the levels in 27 healthy donors. Patients with anaphylaxis indeed exhibited substantially lower levels of the lipid mediator (a mean level of 142.3 ± 14.11 pg/mL) compared with the controls (a mean level of 324.7 ± 33.73 pg/mL) (Fig 1, A). When only the group of patients with anaphylaxis was

Discussion

PGE2 is the most versatile and pleiotropic eicosanoid mediator.35, 36, 37 Studies in the past few decades have suggested a protective role of COX and PGE2 in the precipitation of allergic symptoms.38, 39, 40, 41 Our work on the anaphylaxis registry revealed COX inhibitors as facilitators of allergic responses; hence their classification as (extrinsic) cofactors.8

The aim of this study was to delineate whether the PGE2 network may have a more general role in anaphylaxis. We first demonstrated

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    This work was supported by grants from the Deutsche Forschungsgemeinschaft to M.W. (WO 541/16-1 and 16-2).

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    These authors shared the role of first author.

    These authors shared the role of senior author.

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