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

• Final Report Year: 2024

Final Report Abstract

Acetylsalicylic acid (ASA) is an inhibitor of cyclooxygenases (COX) with known proanaphylactic effects. Cyclooxygenase catalyzes the synthesis of among others prostaglandin E2 (PGE2), which is thought to play a major role in the susceptibility and intensity of allergic reactions. PGE2 deficiency was previously reported by us for the first time to correlate with an increased severity of anaphylaxis. The aim of this project was to investigate whether and how the pro-anaphylactic effect of ASA depends on PGE2. In a passive systemic anaphylaxis (PSA) model, we demonstrate that ASA-mediated anaphylaxis aggravation can be counteracted with pharmacological inhibition of PGE2 degradation. Furthermore, agonists of PGE2 specific E-type prostanoid (EP) receptors induced a partially (EP2, EP4) or complete (EP3) reversion of ASA aggravated anaphylaxis. The knockout of EP2, EP3 or EP4 displayed no significant aggravation of the anaphylactic reactions and suggested that each of the receptors individually contributes to ASA susceptibility. Using human ex vivo experiments and in vivo allergen challenges, we were able to confirm the influence of ASA on mast cell reactivity and the direct role of EP receptors in mast cell activation. In allergy sufferers, prior ingestion of ASA increased skin response to allergens but not to histamine. In contrast, the responses of basophils to ex vivo FcεRI aggregation remained unchanged, suggesting that ASA increases the stimulatory ability of mast cells in a PGE2-dependent manner. Taken together, our data confirm the central role of PGE2 in ASA-enhanced anaphylaxis and open up targeted EP receptor activation as a target to influence the expression of an anaphylactic response.

Publications

• Serum levels of 9α,11β‐PGF2 and apolipoprotein A1 achieve high predictive power as biomarkers of anaphylaxis. Allergy, 72(11), 1801-1805.
  Wittenberg, M.; Nassiri, M.; Francuzik, W.; Lehmann, K.; Babina, M. & Worm, M.
  
• PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness. Journal of Allergy and Clinical Immunology, 146(6), 1387-1396.e13.
  Rastogi, Shruti; Willmes, Diana Maria; Nassiri, Maria; Babina, Magda & Worm, Margitta
  
• Different phenotypes of drug‐induced anaphylaxis—Data from the European Anaphylaxis Registry. Allergy, 78(6), 1615-1627.
  Hanschmann, Theresa; Francuzik, Wojciech; Dölle‐Bierke, Sabine; Hofmeier, Kathrin Scherer; Grabenhenrich, Linus; Ruëff, Franziska; Renaudin, Jean‐Marie; Pföhler, Claudia; Treudler, Regina; Bilò, M. Beatrice; Lang, Roland; Ensina, Luis Felipe; Christoff, George; Cardona, Victoria; Wagner, Nicola; Reider, Norbert; Müller, Sabine; Dickel, Heinrich & Worm, Margitta
  
• Diversities of allergic pathologies and their modifiers: Report from the second DGAKI-JSA meeting. Allergology International, 71(3), 310-317.
  Asano, Koichiro; Tamari, Mayumi; Zuberbier, Torsten; Yasudo, Hiroki; Morita, Hideaki; Fujieda, Shigeharu; Nakamura, Yuumi; Traidl, Stephan; Hamelmann, Eckard; Raap, Ulrike; Babina, Magda; Nagase, Hiroyuki; Okano, Mitsuhiro; Katoh, Norito; Ebisawa, Motohiro; Renz, Harald; Izuhara, Kenji & Worm, Margitta
  
• Serological profiling reveals hsa-miR-451a as a possible biomarker of anaphylaxis. JCI Insight, 7(7).
  Francuzik, Wojciech; Pažur, Kristijan; Dalke, Magdalena; Dölle-Bierke, Sabine; Babina, Magda & Worm, Margitta
  
• Food-Induced Anaphylaxis: Data From the European Anaphylaxis Registry. The Journal of Allergy and Clinical Immunology: In Practice, 11(7), 2069-2079.e7.
  Dölle-Bierke, Sabine; Höfer, Veronika; Francuzik, Wojciech; Näher, Anatol-Fiete; Bilo, Maria Beatrice; Cichocka-Jarosz, Ewa; Lopes, de Oliveira Lucila C.; Fernandez-Rivas, Montserrat; García, Blanca E.; Hartmann, Karin; Jappe, Uta; Köhli, Alice; Lange, Lars; Maris, Ioana; Mustakov, Tihomir Bogdanov; Nemat, Katja; Ott, Hagen; Papadopoulos, Nikolaos G.; Pföhler, Claudia ... & Worm, Margitta
  
• Occupational anaphylaxis—Data from the anaphylaxis registry. Allergy, 79(3), 702-710.
  Worm, Margitta; Höfer, Veronika; Dölle‐Bierke, Sabine; Bilo, Maria Beatrice; Hartmann, Karin; Sabouraud‐Leclerc, Dominique & Treudler, Regina
  
• Fatal and Near-Fatal Anaphylaxis: Data From the European Anaphylaxis Registry and National Health Statistics. The Journal of Allergy and Clinical Immunology: In Practice, 12(1), 96-105.e8.
  Höfer, Veronika; Dölle-Bierke, Sabine; Francuzik, Wojciech; Ruëff, Franziska; Sabouraud-Leclerc, Dominique; Treudler, Regina; Moeser, Anne; Hartmann, Karin; Pföhler, Claudia; Wagner, Nicola; Ensina, Luis Felipe; Wedi, Bettina; Cardona, Victoria & Worm, Margitta
  
• Acetylsalicylic acid aggravates anaphylaxis in a PGE2-dependent manner. Journal of Clinical Investigation, 135(5).
  Globig, Philipp; Morakabati, Payam; Höfer, Veronika; Willmes, Diana M.; Babina, Magda & Worm, Margitta