title: The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype.
abstract: Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-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 13S,14S-epoxy-docosa-4Z,7Z,9E,11E,16Z,19Z-hexaenoic acid (13S,14S-epoxy-DHA) was prepared, and its stereochemistry was confirmed by NMR spectroscopy. When this 13S,14S-epoxide was incubated with human macrophages, it was converted to MaR1. The synthetic 13S,14S-epoxide inhibited leukotriene B4 (LTB4) formation by human leukotriene A4 hydrolase (LTA4H) ∼40% (P<0.05) to a similar extent as LTA4 (∼50%, P<0.05) but was not converted to MaR1 by this enzyme. 13S,14S-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 13S,14S-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.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Nikita A
authors.initials: NA
authors.lastname: Vlasenko
authors.forename: Bin
authors.initials: B
authors.lastname: Deng
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000378:metabolism*; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D007975:Leukotriene B4; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D001092:Arachidonate 12-Lipoxygenase; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
keywords: DHA; inflammation resolution; leukocytes; n-3 omega essential fatty acids; proresolving mediators