Does the deficiency of prostaglandin E2 predispose to anaphylaxis?
Published: May 11, 2020
Prostaglandins are potent lipid-derived mediators orchestrating communication between cells. Prostaglandin E2 (PGE2), the most abundant among them, mediates fever and pain, and interference with its generation is a major effect of painkillers like Aspirin and Ibuprofen. In fact, substances dampening PGE2 production are the most commonly used drugs in the world. On the other hand, PGE2 plays a number of homeostatic functions that are generally beneficial such as gastrointestinal protection and in the context of stem cell and immune regulation, settings in which the prostaglandin safeguards health.
Anaphylaxis (ANA) is the most severe form of an acute allergic reaction. Drugs that suppress prostaglandin production can act as co-factors of ANA, thereby facilitating its manifestation. Aggravation by these drugs is likewise common in other atopic spectrum disorders like asthma. Variable ANA sensitivities are observed across humans and mouse strains, which underscores the importance of genetic signatures that influence the occurrence and course of an allergic reaction.
This study, published by Rastogi et al. in The Journal of Allergy & Clinical Immunology (JACI), demonstrates for the first time that patients susceptible to suffering an ANA episode have an impaired PGE2 system. Comparing ANA patients and healthy controls side-by-side, Rastogi and colleagues report that diminished PGE2 levels are a hallmark of ANA independent of drug intake, while other prostaglandins show slight or inverse changes. In a complementary way, they find that ANA susceptibility also depends on PGE2 levels in two mouse strains.
Increase in PGE2 by provision of the prostaglandin itself or an inhibitor of the PGE2 degrading enzyme alleviates ANA severity in a mouse model. In addition, agonists of the PGE2 receptors EP2 or EP4 also protect mice against ANA. Mast cells are the critical effector cells of ANA, as their mediators, released on contact with the allergen, precipitate the symptoms of ANA. The study shows that PGE2 interferes with mast cell activation by dampening their stimulability through EP2 and EP4 receptors. Accordingly, EP2 and, more so, EP4 are highly expressed by mast cells. Mechanistically, PGE2 interferes with the phosphorylation of two proteins involved in the signaling cascades initiated upon mast cell activation, namely phospholipase C gamma-1 (PLCy1) and extracellular-signal regulated kinase (ERK).
This study provides evidence that PGE2 deficiency can dictate susceptibility towards ANA in part by facilitating mast cell activation and it highlights the potential use of inhibitors of PGE2 degradation, EP2 or EP4 agonists as therapeutic or preventive strategies in ANA patients. Future studies will have to explore the reasons behind the aberrant regulation of PGE2 in the context of ANA and examine whether selective targeting of the PGE2 system holds promise for the management of this life-threatening condition.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
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