Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome
Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome
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DOI：
10.1096/fj.201802509r
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发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Gerstmeier, Jana
中科院分区：
文献类型：
--
作者：
Werner, Markus;Jordan, Paul M.;Gerstmeier, Jana
非甾体类抗炎药通过靶向环加氧酶（COX）、5-脂氧合酶（LOX）或5-LOX活化蛋白（FLAP），干扰花生四烯酸代谢为促炎性β-肾上腺素和白三烯。这些和相关的酶与复合脂质介体（LM）网络内的显著串扰一起起作用，其中还形成专门的前分辨LM（SPM）。在这里，我们提出了如何突出的LM途径可以在人类促炎M1和proresolving M2巨噬细胞表型，暴露于大肠杆菌，产生丰富的白藜芦醇和白三烯（M1）或SPM（M2）的差异调制。应用基于靶向液相色谱-串联质谱的代谢脂质组学分析和定量特定的LM谱。除了预期的目标行动外，我们还发现：1）考克斯或15-LOX-1抑制剂升高炎性白三烯水平，2）FLAP和5-LOX抑制剂减少M1中的白三烯，但在M2巨噬细胞中减少较少，3）齐留通阻断消退起始SPM生物合成，而FLAP抑制增加SPM水平，和4）15-LOX-1抑制剂3887抑制M2巨噬细胞中SPM的形成。总之，干扰不同巨噬细胞表型中的离散LM生物合成酶会显著影响LM代谢组，并对炎症消退药物治疗产生潜在影响。我们的数据可以更好地评估这些药物干预炎症性疾病的治疗潜力。乔丹，下午，Romp，E.，Czapka，A.，Rao，Z.，Kretzer，C.，Koeberle，A.，加尔夏大学，佩斯，S.，Claesson，H. E、塞尔汉角N.，Werz，O.，Gerstmeier，J.靶向促炎和促分解脂质代谢组的生物合成网络。
Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX-activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on-target actions, we found that: 1) COX or 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP and 5-LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3) zileuton blocks resolution-initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4) that the 15-LOX-1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.