Human leukocytes selectively convert 4,5-epoxy-resolvin to resolvin D3, resolvin D4, and a cys-resolvin isomer.
Ashley E Shay, Robert Nshimiyimana, Bengt Samuelsson, Nicos A Petasis, Jesper Z Haeggström, Charles N Serhan
Author Information
Ashley E Shay: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115. ORCID
Robert Nshimiyimana: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Bengt Samuelsson: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden; bengt.samuelsson@ki.se cserhan@bwh.harvard.edu.
Nicos A Petasis: Department of Chemistry, Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089. ORCID
Jesper Z Haeggström: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden. ORCID
Charles N Serhan: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; bengt.samuelsson@ki.se cserhan@bwh.harvard.edu. ORCID
Human phagocytes have key functions in the resolution of inflammation. Here, we assessed the role of the proposed 4,5-epoxy-resolvin intermediate in the biosynthesis of both resolvin D3 and resolvin D4. We found that human neutrophils converted this synthetic intermediate to resolvin D3 and resolvin D4. M2 macrophages transformed this labile epoxide intermediate to resolvin D4 and a previously unknown cysteinyl-resolvin isomer without appreciable amounts of resolvin D3. M2 macrophages play critical roles in the resolution of inflammation and in wound healing. Human M2 macrophages also converted leukotriene A to lipoxins. The cysteinyl-resolvin isomer significantly accelerated tissue regeneration of surgically injured planaria. In a model of human granuloma formation, the cysteinyl-resolvin isomer significantly inhibited granuloma development by human peripheral blood leukocytes. Together, these results provide evidence for a human cell type-specific role of 4,5-epoxy-resolvin in the biosynthesis of resolvin D3 by neutrophils, resolvin D4 by both M2 macrophages and neutrophils, and a unique cysteinyl-resolvin isomer produced by M2 macrophages that carries potent biological activities in granuloma formation and tissue regeneration.
