Biosynthesis of resolvin D1, resolvin D2, and RCTR1 from 7,8(S,S)- epoxytetraene in human neutrophils and macrophages

• 成果类型: Article
• 署名作者: Nshimiyimana, Robert; Simard, Melissa; Teder, Tarvi; Rodriguez, Ana R.; Spur, Bernd W.; Haeggstroem, Jesper Z.; Serhan, Charles N.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Karolinska Institutet; Rowan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12787
• DOI: 10.1073/pnas.2405821121
• 发表日期: 2024-09-10
• 关键词: stereochemical assignments; tissue regeneration; lipid mediators; ACID; identification; leukocytes; RESOLUTION; autacoids; precursor

摘要

While the acute inflammatory response to harmful stimuli is protective, unrestrained neutrophil swarming drives collateral tissue damage and inflammation. Biosynthesized from omega- 3 essential polyunsaturated fatty acids, resolvins are a family of signaling molecules produced by immune cells within the resolution phase to orchestrate return to homeostasis. Understanding the mechanisms that govern biosynthesis of these potent molecules gives insight into stimulating endogenous resolution and offers fresh opportunities for preventing and treating excessive inflammation. In this report, using materials prepared by total synthesis and liquid chromatography and tandem mass spectrometry- based matching studies, we established the role of 7,8(S,S)- epoxytetraene intermediate in the biosynthesis of resolvin D1, resolvin D2, and the resolvin conjugate in tissue regeneration (RCTR1) by human phagocytes. We demonstrated that this 7,8(S,S)- epoxy- containing intermediate is directly converted to resolvin D2 by human M2- like macrophages and to resolvin D1 and RCTR1 by human macrophages, neutrophils, and peripheral blood mononuclear cells. In addition, both human recombinant soluble epoxide hydrolase (sEH) and the glutathione S- transferase leukotriene C4 synthase (LTC4S) each catalyze conversion of this epoxide to resolvin D1 and RCTR1, respectively. MS3 ion- trap scans and isotope incorporation of 18 O from H 2 18 O with sEH indicated that the oxygen atom at C- 8 in resolvin D1 is derived from water. Results from molecular docking simulations with biosynthetic precursor 17S- hydroperoxy- 4,7,10,13,19- cis- 15- trans- docosahexaenoic acid and the epoxy intermediate were consistent with 5- lipoxygenase production of resolvin D1. Together, these results give direct evidence for the role of resolvin 7,8(S,S)- epoxytetraene intermediate in the endogenous formation of resolution- phase mediators resolvin D1, resolvin D2, and RCTR1 by human phagocytes.