Differential impact of 5-lipoxygenase-activating protein antagonists on the biosynthesis of leukotrienes and of specialized pro-resolving mediators

Philipp Dahlke; Lukas K Peltner; Paul M Jordan; Oliver Werz

doi:10.3389/fphar.2023.1219160

Differential impact of 5-lipoxygenase-activating protein antagonists on the biosynthesis of leukotrienes and of specialized pro-resolving mediators

Front Pharmacol. 2023 Aug 23:14:1219160. doi: 10.3389/fphar.2023.1219160. eCollection 2023.

Authors

Philipp Dahlke¹, Lukas K Peltner¹, Paul M Jordan^{1

2}, Oliver Werz^{1

2}

Affiliations

¹ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany.
² Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Jena, Germany.

Abstract

Lipoxygenases (LOX) transform arachidonic acid (AA, C20:4) and docosahexaenoic acid (DHA, C22:6) into bioactive lipid mediators (LMs) that comprise not only pro-inflammatory leukotrienes (LTs) but also the specialized pro-resolving mediators (SPMs) that promote inflammation resolution and tissue regeneration. The 5-LOX-activating protein (FLAP) is known to provide AA as a substrate to 5-LOX for generating LTs, such as LTB₄, a potent chemoattractant and activator of phagocytes. Notably, 5-LOX is also involved in the biosynthesis of certain SPMs, namely, lipoxins and D-resolvins, implying a role of FLAP in SPM formation. FLAP antagonists have been intensively developed as LT biosynthesis inhibitors, but how they impact SPM formation is a matter of debate. Here, we show that FLAP antagonism suppresses the conversion of AA by 5-LOX to LT and lipoxins, while the conversion of DHA to SPM is unaffected. Screening of multiple prominent FLAP antagonists for their effects on LM formation in human M1- and M2-monocyte-derived macrophages by comprehensive LM profiling showed that all nine compounds reduced the production of 5-LOX-derived LTs but increased the formation of SPMs from DHA, e.g., resolvin D5. Some FLAP antagonists, especially those that contain an indole or benzimidazole moiety, even elicited SPM formation in resting M2-monocyte-derived macrophages. Intriguingly, in coincubations of human neutrophils and platelets that produce substantial AA-derived lipoxin and DHA-derived RvD5, FLAP antagonism abolished lipoxin formation, but resolvin D5 levels remained unaffected. Conclusively, antagonism of FLAP suppresses the conversion of AA by 5-LOX to LTs and lipoxins but not the conversion of DHA by 5-LOX to SPM, which should be taken into account for the development of such compounds as anti-inflammatory drugs.

Keywords: 15-lipoxygenase; 5-lipoxygenase-activating protein; leukotrienes; lipid mediators; lipoxins; macrophages; metabololipidomics; specialized pro-resolving mediators.

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB 1127/3 ChemBioSys, project no. 239748522, and SFB 1278/2 PolyTarget, project no. 316213987.