Libreros Stephania, Shay Ashley E, Nshimiyimana Robert, Fichtner David, Martin Michael J, Wourms Nicholas, Serhan Charles N
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, United States.
Cayman Chemical, Research and Development Department, Ann Arbor, MI, United States.
Front Immunol. 2021 Feb 10;11:631319. doi: 10.3389/fimmu.2020.631319. eCollection 2020.
The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5,15-dihydroxy-6,8,11,13E,17-eicosapentaenoic acid and its bioactions in human phagocyte response.
急性炎症反应的消退取决于吞噬细胞积极清除凋亡细胞和病原体。在炎症消退过程中，特异性促消退介质（SPM）的生物合成对于其在先天免疫细胞中的作用至关重要。消退素E4（RvE4：5S，15S-二羟基-二十碳五烯酸）是从二十碳五烯酸（EPA）生物合成的E系列消退素中的一个新发现成员，最近在生理性缺氧中得到阐明。鉴于其能够增加巨噬细胞对凋亡细胞的胞葬作用，这种新的消退素被命名为RvE4。在此，我们报道了RvE4的全有机合成，证实了其独特结构、完整的立体化学归属和功能。这种合成的RvE4与生物源RvE4物质的物理性质相匹配，即紫外（UV）吸收、色谱行为、串联质谱（MS）碎裂以及生物活性。我们证实了RvE4对人凋亡中性粒细胞和衰老红细胞的人M2巨噬细胞胞葬作用具有强效反应。总之，这些结果为将RvE4的完整立体化学归属为5,15-二羟基-6,8,11,13E,17-二十碳五烯酸及其在人吞噬细胞反应中的生物作用提供了直接证据。
