Maresin-like Lipid Mediators Are Produced by Leukocytes and Platelets and Rescue Reparative Function of Diabetes-Impaired Macrophages

Summary Nonhealing diabetic wounds are associated with impaired macrophage (Mf) function. Leukocytes and platelets (PLT) play crucial roles in wound healing by poorly understood mechanisms. Here we report the identification and characterization of the maresin-like(L) mediators 14,22-dihydroxy-docosa-4 Z ,7 Z ,10 Z ,12 E ,16 Z ,19 Z -hexaenoic acids, 14 S ,22-diHDHA (maresin-L1), and 14 R ,22-diHDHA (maresin-L2) that are produced by leukocytes and PLT and involved in wound healing. We show that 12-lipoxygenase-initiated 14 S -hydroxylation or cytochrome P450 catalyzed 14 R -hydroxylation and P450-initiated ω(22)-hydroxylation are required for maresin-L biosynthesis. Maresin-L treatment restores reparative functions of diabetic Mfs, suggesting that maresin-Ls act as autocrine/paracrine factors responsible for, at least in part, the reparative functions of leukocytes and PLT in wounds. Additionally, maresin-L ameliorates Mf inflammatory activation and has the potential to suppress the chronic inflammation in diabetic wounds caused by activation of Mfs. These findings provide initial insights into maresin-L biosynthesis and mechanism of action and potentially offer a therapeutic option for better treatment of diabetic wounds.