| Summary: | 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 <sup>1</sup>H NMR-based metabolomics was employed to identify metabolic pathways that are differentially modulated following primary human monocyte-derived MΦ activation with pro-inflammatory (M1) or anti-inflammatory (M2a) stimuli relative to resting (M0) MΦs. The metabolic profiling of M1 MΦs indicated a substantial increase in oxidative stress as well as a decrease in mitochondrial respiration. These metabolic profiles also provide compelling evidence that M1 MΦs divert metabolites from <i>de novo</i> glycerophospholipid synthesis to inhibit oxidative phosphorylation. Furthermore, glycolysis and lactic acid fermentation were significantly increased in both M1 and M2a MΦs. These metabolic patterns highlight robust metabolic activation markers of MΦ phenotypes. Overall, our study generates additional support to previous observations, presents novel findings regarding the metabolic modulation of human MΦs following activation, and contributes new knowledge to the rapidly evolving field of immunometabolism.
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