Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation
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- 1 July 2010
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 185 (1), 605-614
- https://doi.org/10.4049/jimmunol.0901698
Abstract
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.Keywords
This publication has 56 references indexed in Scilit:
- Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasisGenes & Development, 2010
- Differentiation Stage-Specific Requirement in Hypoxia-Inducible Factor-1α–Regulated Glycolytic Pathway during Murine B Cell Development in Bone MarrowThe Journal of Immunology, 2009
- Differential regulation of HIF-1α isoforms in murine macrophages by TLR4 and adenosine A2A receptor agonistsJournal of Leukocyte Biology, 2009
- Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription FactorThe Journal of Immunology, 2009
- Reactome knowledgebase of human biological pathways and processesNucleic Acids Research, 2008
- Feeding Our Immune System: Impact on MetabolismJournal of Immunology Research, 2008
- The macrophage: Past, present and futureEuropean Journal of Immunology, 2007
- Monocyte and macrophage heterogeneityNature Reviews Immunology, 2005
- Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray ExperimentsStatistical Applications in Genetics and Molecular Biology, 2004
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003