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

Abstract

SUMMARY Non-healing 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 identification and characterization of novel maresin-like(L) mediators 14,22-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acids, 14S,22-diHDHA (maresin-L1) and 14R,22-diHDHA (maresin-L2) that are produced by leukocytes and PLT and involved in wound healing. We show that 12-lipoxygenase-initiated 14S-hydroxylation or cytochrome P450 catalyzed 14R-hydroxylation, and P450-initiated ω(22)-hydroxylation are required for maresin-Ls biosynthesis. Maresin-L treatment restores reparative functions to 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 Mfs inflammatory activation and have 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.

Synthesis of Two Stereoisomers of Potentially Bioactive 13,19,20-Trihydroxy Derivative of Docosahexaenoic Acid

“…3 Subsequently, the compound was synthesized, and the structure was determined. 4 Similar properties were then found in new metabolite 2 ('maresin like'), 5 and the structure of 2 was also determined after organic synthesis as well. 6 We then envisaged that hydroxylated compound 3 would possess similar activities because of the structural similarity in the positions of the hydroxylated carbon atoms relative to those in 1 and 2.…”

Oxygenation of polyunsaturated fatty acids and oxidative stress within blood platelets

“…The main metabolite, 14-OH-22:6, has been clearly shown of interest for being the most potent to antagonize the pro-aggregatory and vaso-constricting effects of TxA 2 on platelets and smooth muscle cells, respectively [30,31]. In addition, it has been reported that some maresins from DHA (14S,22-diHDoHA (maresin-L1) and 14R,22-diHDoHA (maresin-L2)) are produced by both platelets and leukocytes, and partly responsible for reparative functions of these cells in wounds [32]. Docosapentaenoic acids, 22:5n-3 and 22:5n-6 are also good substrates of platelet 12-LOX, and the former behaves like DHA with its conversion into 11-and 14-OH derivatives, whereas 22:5n-6 is only converted into 14-OH-22:5 [33].…”

Unified nexus of macrophages and maresins in cardiac reparative mechanisms

“…MaR-1 is effective in controlling inflammation in periodontal infections with unresolved inflammation and leukocyte-mediated tissue destruction (108), and restoring the reparative function of nonhealing diabetic wounds impaired the macrophages (109). MaR-1 has also been tested in the treatment of diabetic nephropathy by inhibiting nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing-3 and controls the inflammation rate in renal failure (110).…”