Identification and Complete Stereochemical Assignments of the New Resolvin Conjugates in Tissue Regeneration in Human Tissues that Stimulate Proresolving Phagocyte Functions and Tissue Regeneration
Identification and Complete Stereochemical Assignments of the New Resolvin Conjugates in Tissue Regeneration in Human Tissues that Stimulate Proresolving Phagocyte Functions and Tissue Regeneration
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DOI：
10.1016/j.ajpath.2018.01.004
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发表时间：
2018-04-01
影响因子：
6
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
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作者：
de la Rosa, Xavier;Norris, Paul C.;Serhan, Charles N.
组织再生中的解决素结合物(RCTRs)是一种新的化学信号，可以加速炎症、感染和组织再生的消退。在此，我们利用基于高效液相-串联质谱仪的代谢脂组学方法，在人的脾、淋巴结、骨髓和脑中鉴定了RCTRs。在与金黄色葡萄球菌孵育的人脾中，内源性RCTR随着氚标记的二十二碳六烯酸的转化而增加，从而激活了途径。内源RCTRs的物理和生物学特性与全有机合成制备的RCTRs相匹配。其全立体化学归属为8R-glutathionyl-7S，17S-dihydroxy-4Z，9E，11E，13Z，15E，19Z-docosahexaenoic酸，RCTR2为8R-cysteinylglycinyl-7S，17S-dihydroxy-4Z，9E，11E，13Z，15E，19Z-docosahexaenoic酸，RCTR3为8R-cysteinyt-7S，17S-dihydroxy-4Z，9E，11E，13Z，15E，19Z-docosahexaenoic酸。这些立体化学定义的RCTRs刺激人巨噬细胞吞噬、泡腾和扁平线虫组织生成。蛋白质组图谱显示，RCTRs调节人巨噬细胞的前炎性和抗炎性细胞因子。在微流体室中，三种RCTR限制了人多形核细胞的迁移。在后肢缺血再灌注所致的脏器损伤中，RCTR2和RCTR3均减少了多形核细胞在肺内的浸润。在感染性腹膜炎中，RCTR1缩短了缓解间期。每种RCTR(1nmoL/L)均可使车前草组织再生加快约0.5天，这与大树脂素和保护素CTR有直接的对比。总之，这些结果在人体组织中鉴定了一种新的生物活性RCTR(即RCTR3)，并建立了三种RCTR在体内的完整立体化学和秩序势。此外，RCTR1、RCTR2和RCTR3对人类白细胞都有很强的抗炎和促溶解作用。
Resolvin conjugates in tissue regeneration (RCTRs) are new chemical signals that accelerate resolution of inflammation, infection, and tissue regeneration. Herein, using liquid chromatography-tandem mass spectrometry-based metabololipidomics, we identified RCTRs in human spleen, lymph node, bone marrow, and brain. In human spleen incubated with Staphylococcus aureus, endogenous RCTRs were increased along with conversion of deuterium-labeled docosahexaenoic acid, conferring pathway activation. Physical and biological properties of endogenous RCTRs were matched with those prepared by total organic synthesis. The complete stereochemicaL assignment of bioactive RCTR1 is 8R-glutathionyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, RCTR2 is 8R-cysteinylglycinyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, and RCTR3 is 8R-cysteinyt-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid. These stereochemically defined RCTRs stimulated human macrophage phagocytosis, efferocytosis, and planaria tissue generation. Proteome profiling demonstrated that RCTRs regulated both proinftammatory and anti-inflammatory cytokines with human macrophages. In microfluidic chambers, the three RCTRs limited human polymorphonuclear cell migration. In hind-Limb ischemia-reperfusion-initiated organ injury, both RCTR2 and RCTR3 reduced polymorphonuclear cell infiltration into lungs. In infectious peritonitis, RCTR1 shortened the resolution intervals. Each RCTR (1 nmol/L) accelerated planaria tissue regeneration by approximately 0.5 days, with direct comparison to both maresin and protectin CTRs. Together, these results identify a new bioactive RCTR (ie, RCTR3) in human tissues and establish the complete stereochemistry and rank-order potencies of three RCTRs in vivo. Moreover, RCTR1, RCTR2, and RCTR3 each exert potent anti-inflammatory and proresolving actions with human leukocytes.