Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation

By Juan-Carlos Rodríguez-Prados, Paqui G Través, J. Cuenca, Daniel Rico, Julián Aragonés, P. Martín-Sanz, Marta Cascante, L. Boscá. Journal of Immunology, 2010

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Macrophages play a relevant role in innate and adaptive immunity depending on the balance of the stimuli received. From an analytical and functional point of view, macrophage stimulation can be segregated into three main modes, as follows: innate, classic, and alternative pathways. These differential activations result in the expression of specific sets of genes involved in the release of pro- or anti-inflammatory stimuli. In the present work, we have analyzed whether specific metabolic patterns depend on the signaling pathway activated. A [1,2-13C2]glucose tracer-based metabolomics approach has been used to characterize the metabolic flux distributions in macrophages stimulated through the classic, innate, and alternative pathways. Using this methodology combined with mass isotopomer distribution analysis of the new formed metabolites, the data show that activated macrophages are essentially glycolytic cells, and a clear cutoff between the classic/innate activation and the alternative pathway exists. Interestingly, macrophage activation through LPS/IFN-γ or TLR-2, -3, -4, and -9 results in similar flux distribution patterns regardless of the pathway activated. However, stimulation through the alternative pathway has minor metabolic effects. The molecular basis of the differences between these two types of behavior involves a switch in the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) from the liver type-PFK2 to the more active ubiquitous PFK2 isoenzyme, which responds to Hif-1α activation and increases fructose-2,6-bisphosphate concentration and the glycolytic flux. However, using macrophages targeted for Hif-1α, the switch of PFK2 isoenzymes still occurs in LPS/IFN-γ–activated macrophages, suggesting that this pathway regulates ubiquitous PFK2 expression through Hif-1α-independent mechanisms.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4745b9e1d1ed2f441b75d35f6c5c7718a98c5e9f

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Citations in the corpus

THE INTERLEUKIN-1 FAMILY: BACK TO THE FUTURE (2013, positive): “IL-1 is likely to orient macrophages to aerobic glycolysis as lipopolysaccharide (LPS) does (Rodrı́guez-Prados et al., 2010) and in turn it is downstream of metabolic responses elicited by microbial sensing.”
Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. (2015, background): “The metabolism of M1 macrophages is characterized by increased glycolytic flux and reduced mitochondrial oxidative phosphorylation compared to M0 cells (Rodrı́guez-Prados et al., 2010).”
Microglial M1/M2 polarization and metabolic states (2016, background): “This switch increases glucose uptake and lactate production (Krawczyk et al., 2010; Rodríguez-Prados et al., 2010) with activation of the pentose phosphate pathway (PPP) and decreased mitochondrial oxygen consumption (Haschemi et al., 2012).”
Metabolic Reprograming in Macrophage Polarization (2014, background): “Similarly, forcing oxidative metabolism in an M1 macrophage potentiates the M2 phenotype (12, 13).”
Metabolic Regulation of Immune Responses (2014, background): “reported that the switch to glycolytic metabolism in CAMs was regulated by the phosphofructokinase 2 (PFK2) PFKFB3, which converts fructose-6-phosphate to fructose-2,6-biphosphate to stimulate glycolytic flux (73).”
From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation (2014, background): “Moreover, M1 and M2 macrophages have distinct features in terms of chemokine production profiles (171), and iron and glucose metabolism (172, 173).”
The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases (2016, background): “The glycolytic flux is favourable in classical M1 macrophages phenotype that involves the expression changes of 6-phospho2-kinase isoforms from liver-type to more active ubiquitous isoenzyme, thereby maintaining the level of fructose-2,6bisphosphate [15].”