Cyclooxygenasen as modulators of allergic responses, mechanistic background and therapeutic potential

• Applicant: Professorin Dr. Margitta Worm
• Subject Area: Dermatology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264921598

Cyclooxygenase (COX) inhibitors (COXi) are widely employed with an estimated 30 million people using them daily. Allergic diseases are prevalent (≈30% in industrialized countries), but while there is clear evidence for an aggravating role of COXi in allergic disease, the molecular networks establishing this link are highly complex, as underscored by the high level of discrepant and conflicting reports published in this area.Our starting point was that COXi exacerbates anaphylaxis (ANA) in a mouse model by priming mast cells (MCs) towards increased responsiveness. We theorized that the lack of PGE2 was responsible for the effect. The first funding period revealed that this hypothesis was indeed correct, and even more than that: In fact, both exogenous and endogenous PGE2 completely restored ANA severity to the baseline level or went beyond. Likewise, ligation of the three PGE2 receptors EP2, EP3 and EP4 with selective agonists had a moderating effect on ANA.Because EP3 ligation curbed MC activity in vivo, but enhanced it in vitro, an indirect EP3 driven circuit had to be incorporated into our extended hypothesis. Together, there are three routes by which PGE2 restrains MC activity: EP2 and EP4 suppress MCs cell-autonomously, while EP3 dampens MCs via an intermediary. Efficiency and uniform directionality of the different systems offer an explanation for the immense efficacy of PGE2 to prevent ANA.In the skin prick test, Aspirin also lowered the threshold of skin MC activation, verifying the significance and broadness of COXi-enhanced responses to allergen also in humans.Intriguingly, the project discovered that ANA patients exhibit strikingly reduced PGE2 levels even at baseline, suggesting that PGE2 reduction is a general hallmark and perhaps driver of ANA not only upon COXi but also by intrinsic factors that cause the relative PGE2 depletion and thereby predispose to ANA.Collectively, PGE2 seems intimately connected to human and murine ANA propensity and severity. The second funding period aims to finalize and hone the current findings with the use of knockout strategies in vivo, supplemented with in vitro approaches on primary MCs embedded in complex systems to identify the role of each EP entity and pinpoint the sequence of events as comprehensively as possible. Through a candidate pathway approach, we also integrate a pilot study to start analyzing the genetic underpinnings of PGE2 diminution in the context of ANA. This will facilitate pre-symptomatic diagnosis of at-risk individuals and the implementation of preventive and treatment measures (such as PGE2-augmenting activities) in the longer run. With this project, we aim to help disentangle the complex network of the PGE2-allergy connection and unearth some of its major elements.

• DFG Programme: Research Grants