The novel 13 S ,14 S ‐epoxy‐maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A 4 hydrolase (LTA 4 H), and shifts macrophage phenotype

Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7 R ,14 S ‐dihydroxy‐docosa‐4 Z ,8 E ,10 E ,12 Z ,16 Z ,19 Z ‐hexaenoic acid) is the first identified maresin. Here, we investigate formation, stereochemistry, and precursor role of 13,14‐epoxy‐docosahexaenoic acid, an intermediate in MaR1 biosynthesis. The 14‐lipoxygenation of DHA by human macrophage 12‐lipoxygenase (hm12‐LOX) gave 14‐hydro(peroxy)‐docosahexaenoic acid (14‐HpDHA), as well as several dihydroxy‐docosahexaenoic acids, implicating an epoxide intermediate formation by this enzyme. Using a stereo‐controlled synthesis, enantiomerically pure 13 S ,14 S ‐epoxy‐docosa‐4 Z ,7 Z ,9 E ,11 E ,16 Z ,19 Z ‐hexaenoic acid (13 S ,14 S ‐epoxy‐DHA) was prepared, and its stereochemistry was confirmed by NMR spectroscopy. When this 13 S ,14 S ‐epoxide was incubated with human macrophages, it was converted to MaR1. The synthetic 13 S ,14 S ‐epoxide inhibited leukotriene B 4 (LTB 4 ) formation by human leukotriene A 4 hydrolase (LTA 4 H) ~40% ( P <0.05) to a similar extent as LTA4 (~50%, P <0.05) but was not converted to MaR1 by this enzyme. 1 3S ,14 S ‐epoxy‐DHA also reduced (~60%; P <0.05) arachidonic acid conversion by hm12‐LOX and promoted conversion of M1 macrophages to M2 phenotype, which produced more MaR1 from the epoxide than M1. Together, these findings establish the biosynthesis of the 13 S ,14 S ‐epoxide, its absolute stereochemistry, its precursor role in MaR1 biosynthesis, and its own intrinsic bioactivity. Given its actions and role in MaR1 biosynthesis, this epoxide is now termed 13,14‐epoxy‐maresin (13,14‐eMaR) and exhibits new mechanisms in resolution of inflammation in its ability to inhibit proinflammatory mediator production by LTA4 hydrolase and to block arachidonate conversion by human 12‐LOX rather than merely terminating phagocyte involvement.—Dalli, J., Zhu, M., Vlasenko, N. A., Deng, B., Haeggström, J. Z., Petasis, N. A., Serhan, C. N. The novel 13 S ,14 S ‐epoxy‐maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H) and shifts macrophage phenotype. FASEB J. 27, 2573–2583 (2013). www.fasebj.org