2. Academic Validation
  3. Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages

Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages

  • Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12232-12237. doi: 10.1073/pnas.1607003113.
Jesmond Dalli 1,  Iliyan Vlasakov 2,  Ian R Riley 2,  Ana R Rodriguez 3,  Bernd W Spur 3,  Nicos A Petasis 4,  Nan Chiang 2,  Charles N Serhan 5
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
  • 3 Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084.
  • 4 Department of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, CA 90089.
  • 5 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.
PMID: 27791009 DOI: 10.1073/pnas.1607003113
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 LTC4 and 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.

Keywords

eicosanoids; inflammation; omega-3 fatty acids; proresolving mediators; regeneration.

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