Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

Abstract

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-γ 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-MØ) or M-CSF (M-MØ), which do not release pro- or anti-inflammatory cytokines unless subjected to additional activating stimuli. Compared to M-MØ, GM-MØ displayed higher oxygen consumption rate and aerobic glycolysis (extracellular acidification rate [ECAR]), as well as higher expression of genes encoding glycolytic enzymes. However, M-MØ 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-MØ. The physiological significance of these results became evident under low oxygen tensions, as hypoxia enhanced ECAR in M-MØ via HIF-1α and HIF-2α, increased expression of glycolytic enzymes and GM-MØ–specific genes, and diminished expression of M-MØ–associated genes. Therefore, our data indicate that GM-MØ and M-MØ display distinct bioenergetic profiles, and that hypoxia triggers a transcriptomic switch in macrophages by promoting a HIF-1α/HIF-2α-dependent increase in ECAR.

BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases

“…Our findings indicating (i) reduced ECAR levels as a result of BCAT1 inactivation in human macrophages and (ii) anti-inflammatory effects of ERG240, reversing the M1-like transcriptome in mouse peritoneal macrophages, argue in favour of the involvement of BCAA in M1/proinflammatory macrophage function. Although the metabolic response of murine macrophages and dendritic cells to LPS stimulation has been thoroughly explored1517, the bioenergetic profile of human macrophages is not well described and recent reports suggest that culturing conditions (M-CSF versus GM-CSF) play an important role in their metabolic reprogramming56. Here, we report that early LPS stimulation of human macrophages resulted in an increase of ECAR, which is indicative of increased glycolytic rate and is consistent with previous results obtained in murine bone marrow derived and peritoneal macrophages15.…”

Hif-1α Knockdown Reduces Glycolytic Metabolism and Induces Cell Death of Human Synovial Fibroblasts Under Normoxic Conditions

“…However, increased glycolysis and HIF-1α activity may also occur under aerobic conditions as demonstrated in cancer cells 4, 32 , and in the inflammatory differentiation of immune cells such as lymphocytes, myeloid cells and different type of fibroblasts 2, 12–14, 25 .…”

The roles of CSFs on the functional polarization of tumor‐associated macrophages

“…These studies showed that M‐CSF‐macrophages exhibit a unique M2‐like phenotype, different to the one of M2a‐c macrophages. A recent study has also reported that differences between human M‐CSF‐ and GM‐CSF‐macrophage properties can be extended to their metabolism . Similar to conventional M2 (elicited by IL‐4 or IL‐13) and M2‐like macrophages (i.e., M2b induced by IL‐1β and M2c induced by IL‐10), M‐CSF‐macrophages produce elevated levels of IL‐10 and low levels of IL‐12.…”