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Quantitative 1H NMR Metabolomics Reveal Distinct Metabolic Adaptations in Human Macrophages Following Differential Activation.

ABSTRACT: Macrophages (M?s) are phagocytic immune cells that are found in nearly all human tissues, where they modulate innate and adaptive immune responses, thereby maintaining cellular homeostasis. M?s display a spectrum of functional phenotypes as a result of microenvironmental and stress-induced stimuli. Evidence has emerged demonstrating that metabolism is not only crucial for the generation of energy and biomolecular precursors, but also contributes to the function and plasticity of M?s. Here, 1D 1H NMR-based metabolomics was employed to identify metabolic pathways that are differentially modulated following primary human monocyte-derived M? activation with pro-inflammatory (M1) or anti-inflammatory (M2a) stimuli relative to resting (M0) M?s. The metabolic profiling of M1 M?s indicated a substantial increase in oxidative stress as well as a decrease in mitochondrial respiration. These metabolic profiles also provide compelling evidence that M1 M?s divert metabolites from de novo glycerophospholipid synthesis to inhibit oxidative phosphorylation. Furthermore, glycolysis and lactic acid fermentation were significantly increased in both M1 and M2a M?s. These metabolic patterns highlight robust metabolic activation markers of M? phenotypes. Overall, our study generates additional support to previous observations, presents novel findings regarding the metabolic modulation of human M?s following activation, and contributes new knowledge to the rapidly evolving field of immunometabolism.

SUBMITTER: Fuchs AL

PROVIDER: S-EPMC6918149 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Quantitative <sup>1</sup>H NMR Metabolomics Reveal Distinct Metabolic Adaptations in Human Macrophages Following Differential Activation.

Fuchs Amanda L AL Schiller Sage M SM Keegan Wyatt J WJ Ammons Mary Cloud B MCB Eilers Brian B Tripet Brian B Copié Valérie V

Metabolites 20191024 11

Macrophages (MΦs) are phagocytic immune cells that are found in nearly all human tissues, where they modulate innate and adaptive immune responses, thereby maintaining cellular homeostasis. MΦs display a spectrum of functional phenotypes as a result of microenvironmental and stress-induced stimuli. Evidence has emerged demonstrating that metabolism is not only crucial for the generation of energy and biomolecular precursors, but also contributes to the function and plasticity of MΦs. Here, 1D <s ...[more]

PMID: 31652958

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Project description:BackgroundOpium poppy (Papaver somniferum) produces a diverse array of bioactive benzylisoquinoline alkaloids and has emerged as a model system to study plant alkaloid metabolism. The plant is cultivated as the only commercial source of the narcotic analgesics morphine and codeine, but also produces many other alkaloids including the antimicrobial agent sanguinarine. Modulations in plant secondary metabolism as a result of environmental perturbations are often associated with the altered regulation of other metabolic pathways. As a key component of our functional genomics platform for opium poppy we have used proton nuclear magnetic resonance (1H NMR) metabolomics to investigate the interplay between primary and secondary metabolism in cultured opium poppy cells treated with a fungal elicitor.ResultsMetabolite fingerprinting and compound-specific profiling showed the extensive reprogramming of primary metabolic pathways in association with the induction of alkaloid biosynthesis in response to elicitor treatment. Using Chenomx NMR Suite v. 4.6, a software package capable of identifying and quantifying individual compounds based on their respective signature spectra, the levels of 42 diverse metabolites were monitored over a 100-hour time course in control and elicitor-treated opium poppy cell cultures. Overall, detectable and dynamic changes in the metabolome of elicitor-treated cells, especially in cellular pools of carbohydrates, organic acids and non-protein amino acids were detected within 5 hours after elicitor treatment. The metabolome of control cultures also showed substantial modulations 80 hours after the start of the time course, particularly in the levels of amino acids and phospholipid pathway intermediates. Specific flux modulations were detected throughout primary metabolism, including glycolysis, the tricarboxylic acid cycle, nitrogen assimilation, phospholipid/fatty acid synthesis and the shikimate pathway, all of which generate secondary metabolic precursors.ConclusionThe response of cell cultures to elicitor treatment involves the extensive reprogramming of primary and secondary metabolism, and associated cofactor biosynthetic pathways. A high-resolution map of the extensive reprogramming of primary and secondary metabolism in elicitor-treated opium poppy cell cultures is provided.

Dataset Information

Quantitative 1H NMR Metabolomics Reveal Distinct Metabolic Adaptations in Human Macrophages Following Differential Activation.

Publications

Quantitative <sup>1</sup>H NMR Metabolomics Reveal Distinct Metabolic Adaptations in Human Macrophages Following Differential Activation.

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