Isotope Tracing Untargeted Metabolomics Reveals Macrophage Polarization-State-Specific Metabolic Coordination across Intracellular Compartments.
Isotope Tracing Untargeted Metabolomics Reveals Macrophage Polarization-State-Specific Metabolic Coordination across Intracellular Compartments.
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DOI：
10.1016/j.isci.2018.10.029
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发表时间：
2018-11-30
期刊：
影响因子：
5.8
通讯作者：
Crawford PA
中科院分区：
文献类型：
--
作者：
Puchalska P;Huang X;Martin SE;Han X;Patti GJ;Crawford PA
我们应用稳定同位素示踪，基于质谱学的非靶向代谢组学，揭示了骨髓来源的巨噬细胞中13C底物标记的生化空间。在通路水平上，经典的(脂多糖[LPS]极化的，M1)和交替的(IL[IL]-4极化的，M2)极化的巨噬细胞被13C标记，具有惊人的一致性。尿苷二磷酸N-乙酰氨基葡萄糖(UDP-GlcNAc)是氨基己糖生物合成途径的中间产物，在内毒素和IL-4极化的巨噬细胞中同样丰富。13C-同位素的信息学研究表明，内毒素极化的巨噬细胞利用戊糖磷酸途径产生UDP-GlcNAc，而IL-4极化的巨噬细胞依赖完整的葡萄糖和葡萄糖碳的线粒体代谢。来自[13C]葡萄糖的标记被未标记的脂肪酸和乙酰乙酸酯竞争，强调了底物代谢在能量转换之外的广泛作用。最后，脂多糖极化的巨噬细胞代谢产物衣康酸被输入到IL-4极化的巨噬细胞中，在那里它重新编程[13C]葡萄糖代谢。因此，在巨噬细胞中使用完全无监督的同位素示踪代谢组学揭示了极化状态特定的代谢途径的连通性、底物竞争和代谢物在细胞间的分配。经典极化和交替极化的巨噬细胞利用氨基己糖的生物合成多种碳源支持氨基己糖和衣康酸的生物合成细胞内的代谢区划随巨噬细胞极化的不同而不同衣康酸被导入免疫系统的交替极化的巨噬细胞成分中；免疫学；代谢组学
We apply stable isotope tracing, mass-spectrometry-based untargeted metabolomics, to reveal the biochemical space labeled by 13C-substrates in bone-marrow-derived macrophages. At the pathway level, classically (lipopolysaccharide [LPS]-polarized, M1) and alternatively (interleukin [IL]-4-polarized, M2) polarized macrophages were 13C-labeled with surprising concordance. Total pools of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), an intermediate in the hexosamine biosynthetic pathway, were equally abundant in LPS- and IL-4-polarized macrophages. Informatic scrutiny of 13C-isotopologues revealed that LPS-polarized macrophages leverage the pentose phosphate pathway to generate UDP-GlcNAc, whereas IL-4-polarized macrophages rely on intact glucose and mitochondrial metabolism of glucose carbon. Labeling from [13C]glucose is competed by unlabeled fatty acids and acetoacetate, underscoring the broad roles for substrate metabolism beyond energy conversion. Finally, the LPS-polarized macrophage metabolite itaconate is imported into IL-4-polarized macrophages, in which it reprograms [13C]glucose metabolism. Thus, use of fully unsupervised isotope tracing metabolomics in macrophages reveals polarization-state-specific metabolic pathway connectivity, substrate competition, and metabolite allocation among cellular compartments. Classically and alternatively polarized macrophages leverage hexosamine biosynthesis Multiple carbon sources support hexosamine and itaconate biosynthesis Intracellular metabolic compartmentation varies with macrophage polarization Itaconate is imported into alternatively polarized macrophages Components of the Immune System; Immunology; Metabolomics
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影响因子：
46.9
作者：
Guijas C;Montenegro-Burke JR;Warth B;Spilker ME;Siuzdak G
通讯作者：
Siuzdak G
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
14.8
作者：
Chen YJ;Mahieu NG;Huang X;Singh M;Crawford PA;Johnson SL;Gross RW;Schaefer J;Patti GJ
通讯作者：
Patti GJ
代谢组学和同位素跟踪。
影响因子：
64.5
作者：
Jang C;Chen L;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
64.8
作者：
Bambouskova M;Gorvel L;Lampropoulou V;Sergushichev A;Loginicheva E;Johnson K;Korenfeld D;Mathyer ME;Kim H;Huang LH;Duncan D;Bregman H;Keskin A;Santeford A;Apte RS;Sehgal R;Johnson B;Amarasinghe GK;Soares MP;Satoh T;Akira S;Hai T;de Guzman Strong C;Auclair K;Roddy TP;Biller SA;Jovanovic M;Klechevsky E;Stewart KM;Randolph GJ;Artyomov MN
通讯作者：
Artyomov MN