Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

Macrophages integrate information from the tissue microenvironment and adjust their effector functions according to the prevalent extracellular stimuli. Therefore, macrophages can acquire a variety of activation (polarization) states, and this functional plasticity allows the adequate initiation, regulation, and resolution of inflammatory responses. Modulation of the glucose metabolism contributes to the macrophage adaptation to the surrounding cytokine milieu, as exemplified by the distinct glucose catabolism of macrophages exposed to LPS/IFN-gamma or IL-4. To dissect the acquisition of macrophage effector functions in the absence of activating cytokines, we assessed the bioenergetic profile of macrophages generated in the presence of GM-CSF (GM-MO) or M-CSF (M-MO), which do not release pro-or anti-inflammatory cytokines unless subjected to additional activating stimuli. Compared to M-MO, GM-MO displayed higher oxygen consumption rate and aerobic glycolysis (extracellular acidification rate [ECAR]), as well as higher expression of genes encoding glycolytic enzymes. However, M-MO exhibited a significantly higher oxygen consumption rate/ECAR ratio. Surprisingly, whereas aerobic glycolysis positively regulated IL1B, TNF, and INHBA mRNA expression in both macrophage subtypes, mitochondrial respiration negatively affected IL6, IL1B, TNF, and CXCL10 mRNA expression in M-MO. The physiological significance of these results became evident under low oxygen tensions, as hypoxia enhanced ECAR in M-MO via HIF-1 alpha and HIF-2 alpha, increased expression of glycolytic enzymes and GM-MO-specific genes, and diminished expression of M-MO-associated genes. Therefore, our data indicate that GM-MO and M-MO display distinct bioenergetic profiles, and that hypoxia triggers a transcriptomic switch in macrophages by promoting a HIF-1 alpha/HIF-2 alpha-dependent increase in ECAR.