Relevance of the MEK/ERK Signaling Pathway in the Metabolism of Activated Macrophages: A Metabolomic Approach

Abstract

The activation of immune cells in response to a pathogen involves a succession of signaling events leading to gene and protein expression, which requires metabolic changes to match the energy demands. The metabolic profile associated with the MAPK cascade (ERK1/2, p38, and JNK) in macrophages was studied, and the effect of its inhibition on the specific metabolic pattern of LPS stimulation was characterized. A [1,2-[(13)C](2)]glucose tracer-based metabolomic approach was used to examine the metabolic flux distribution in these cells after MEK/ERK inhibition. Bioinformatic tools were used to analyze changes in mass isotopomer distribution and changes in glucose and glutamine consumption and lactate production in basal and LPS-stimulated conditions in the presence and absence of the selective inhibitor of the MEK/ERK cascade, PD325901. Results showed that PD325901-mediated ERK1/2 inhibition significantly decreased glucose consumption and lactate production but did not affect glutamine consumption. These changes were accompanied by a decrease in the glycolytic flux, consistent with the observed decrease in fructose-2,6-bisphosphate concentration. The oxidative and nonoxidative pentose phosphate pathways and the ratio between them also decreased. However, tricarboxylic acid cycle flux did not change significantly. LPS activation led to the opposite responses, although all of these were suppressed by PD325901. However, LPS also induced a small decrease in pentose phosphate pathway fluxes and an increase in glutamine consumption that were not affected by PD325901. We concluded that inhibition of the MEK/ERK cascade interferes with central metabolism, and this cross-talk between signal transduction and metabolism also occurs in the presence of LPS.

Metabolic signatures linked to macrophage polarization: from glucose metabolism to oxidative phosphorylation

“…Our data [7,9,44] and those from other groups support the view that regardless of the challenges used and the availability of alternative energy substrates, macrophage metabolism is by more than 90 % glycolytic, with limited use of other fuels for energy purposes; however, the pathways to generate metabolites by the Krebs cycle and by glutaminolysis are fully functional and used in part for other purposes [7,45]. In this context, we have investigated the role of macrophages in the development of atherogenesis.…”

HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages

“…1E,F). It is well established that PFKFB3 has greater kinase than bisphosphatase activity 26 and thus favors the rise in fructose-2,6-bisphosphate (Fru-2,6-P 2 ), a potent regulator of upper glycolysis that is required for high glycolytic rates 5, 26, 27 .…”

Bioenergetic Profiles Diverge During Macrophage Polarization: Implications for the Interpretation of 18F-FDG PET Imaging of Atherosclerosis

“…Activation of immune cells is associated with enhanced energy demand (20). Therefore, we evaluated whether M1 and M2 polarized macrophages were able to use oxidative phosphorylation as a more efficient and alternative mechanism for ATP generation.…”