title: Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages.
abstract: Macrophages are central in coordinating immune responses, tissue repair, and regeneration, with different subtypes being associated with inflammation-initiating and proresolving actions. We recently identified a family of macrophage-derived proresolving and tissue regenerative molecules coined maresin conjugates in tissue regeneration (MCTR). Herein, using lipid mediator profiling we identified MCTR in human serum, lymph nodes, and plasma and investigated MCTR biosynthetic pathways in human macrophages. With human recombinant enzymes, primary cells, and enantiomerically pure compounds we found that the synthetic maresin epoxide intermediate 13S,14S-eMaR (13S,14S-epoxy- 4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic acid) was converted to MCTR1 (13R-glutathionyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) by LTC4S and GSTM4. Incubation of human macrophages with LTC4S inhibitors blocked LTC4and increased resolvins and lipoxins. The conversion of MCTR1 to MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) was catalyzed by γ-glutamyl transferase (GGT) in human macrophages. Biosynthesis of MCTR3 was mediated by dipeptidases that cleaved the cysteinyl-glycinyl bond of MCTR2 to give 13R-cysteinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid. Of note, both GSTM4 and GGT enzymes displayed higher affinity to 13S,14S-eMaR and MCTR1 compared with their classic substrates in the cysteinyl leukotriene metabolome. Together these results establish the MCTR biosynthetic pathway and provide mechanisms in tissue repair and regeneration.
authors: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Lipid Mediator Unit, Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 2AT, United Kingdom.
authors: Jesmond
authors: J
authors: Dalli
authors: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Iliyan
authors: I
authors: Vlasakov
authors: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Ian R
authors: IR
authors: Riley
authors: Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084.
authors: Ana R
authors: AR
authors: Rodriguez
authors: Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084.
authors: Bernd W
authors: BW
authors: Spur
authors: Department of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, CA 90089.
authors: Nicos A
authors: 0000-0002-8864-4446
authors: NA
authors: Petasis
authors: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Nan
authors: N
authors: Chiang
authors: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; cnserhan@zeus.bwh.harvard.edu.
authors: Charles N
authors: CN
authors: Serhan
mesh_terms: D053898:Biosynthetic Pathways / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000235:genetics / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood / Q000235:genetics*; D008198:Lymph Nodes / Q000254:growth & development / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D015394:Molecular Structure; D012038:Regeneration / Q000235:genetics*; D013237:Stereoisomerism; D014945:Wound Healing / Q000235:genetics
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D004852:Epoxy Compounds; D008055:Lipids; D004281:Docosahexaenoic Acids
keywords: eicosanoids; inflammation; omega-3 fatty acids; proresolving mediators; regeneration