Biological Roles of 5-Oxo-6,8,11,14-Eicosatetraenoic Acid and the OXE Receptor in Allergic Diseases: Collegium Internationale Allergologicum Update 2024

Abstract Background: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-Oxo-ETE) is a metabolite of arachidonic acid shown to promote biological activities in different cell types. Summary: 5-Oxo-ETE is synthesized from the 5-lipoxygenase product 5S-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) in the presence of the nicotinamide adenine dinucleotide phosphate (NADP)+-dependent enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under some conditions that promote oxidation of NADPH to NADP+, such as the respiratory burst in phagocytic cells, eosinophils, and neutrophils, oxidative stress in monocytes and dendritic cells, and cell death, 5-Oxo-ETE synthesis can be dramatically increased. In addition, 5-Oxo-ETE can also be formed in the absence of 5-lipoxygenase in cells through transcellular biosynthesis by inflammatory cell-derived 5S-HETE. This compound performs its biological activities by the highly selective Gi/o-coupled OXE receptor, which is highly expressed on eosinophils, neutrophils, basophils, and monocytes. As such, 5-Oxo-ETE is a potent chemoattractant for these inflammatory cells, especially for eosinophils. Key Messages: Although the pathophysiological role of 5-Oxo-ETE is not clearly understood, 5-Oxo-ETE may be a significant mediator in allergic diseases, such as allergic asthma, allergic rhinitis, and atopic dermatitis. And targeting the OXE receptor may be a novel therapy for this kind of inflammatory condition. Nowadays, selective OXE receptor antagonists are currently under investigation and could become potential therapeutic agents in allergy.