Glycolytic Stimulation Is Not a Requirement for M2 Macrophage Differentiation

Abstract

Enhanced glucose uptake and a switch to glycolysis are key traits of M1 macrophages, whereas enhanced fatty acid oxidation and oxidative phosphorylation are the main metabolic characteristics of M2 macrophages. Recent studies challenge this traditional view, indicating that glycolysis may also be critically important for M2 macrophage differentiation, based on experiments with 2-DG. Here we confirm the inhibitory effect of 2-DG on glycolysis, but also demonstrate that 2-DG impairs oxidative phosphorylation and significantly reduces C-labeled Krebs cycle metabolites and intracellular ATP levels. These metabolic derangements were associated with reduced JAK-STAT6 pathway activity and M2 differentiation marker expression. While glucose deprivation and glucose substitution with galactose effectively suppressed glycolytic activity, there was no effective suppression of oxidative phosphorylation, intracellular ATP levels, STAT6 phosphorylation, and M2 differentiation marker expression. These data indicate that glycolytic stimulation is not required for M2 macrophage differentiation as long as oxidative phosphorylation remains active.

Obesity and ageing: Two sides of the same coin

“…IL‐10 drives the metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) in macrophages. This glycolytic shift is crucial in shaping the phenotypes of macrophages as OXPHOS is important for M2 macrophage differentiation . Therefore, IL‐10 is critical in controlling the overall redox status and polarization of macrophages through regulating autophagy.…”

“…This glycolytic shift is crucial in shaping the phenotypes of macrophages as OXPHOS is important for M2 macrophage differentiation. 67 Therefore, IL-10 is critical in controlling the overall redox status and polarization of macrophages through regulating autophagy. It is worth noting that low levels of IL-10 has been associated with metabolic syndrome 68 , dyslipidaemia, 69 and android obesity.…”

Aminooxyacetic acid attenuates post‐infarct cardiac dysfunction by balancing macrophage polarization through modulating macrophage metabolism in mice

“…Macrophages are typically divided into classically activated M1 subtype and alternatively activated M2 subtype. Classically activated M1 macrophages rely on glycolysis, whereas alternatively activated M2 macrophages acquire energy from OXPHOS . We found that AOAA seems to switch the metabolism of M1 macrophages towards M2‐like metabolism, as displayed by reduction in lactic acid production and glycolytic rates in conjunction with increment in ATP production.…”

Macrophage metabolism: a wound‐healing perspective

“…Blocking glycolysis with 2‐deoxyglucose diminished expression of IL‐4 regulated genes, surface markers and effector functions, and a similar effect was observed when mitochondrial ATP synthesis was inhibited with oligomycin, indicating that glucose can fuel the TCA cycle to support mitochondrial respiration following IL‐4 polarization (Figure ) . However, a recent publication demonstrated that blocking glycolysis via glucose deprivation or galactose supplementation did not affect M(IL‐4) activation, unlike 2‐deoxyglucose treatment . In these settings, IL‐4 activated macrophages could increase the use of alternate pathways, such as glutaminoloysis, to support oxidative metabolism in the absence of glycolytic activity.…”

“…32,45 However, a recent publication demonstrated that blocking glycolysis via glucose deprivation or galactose supplementation did not affect M(IL-4) activation, unlike 2-deoxyglucose treatment. 46 In these settings, IL-4 activated macrophages could increase the use of alternate pathways, such as glutaminoloysis, to support oxidative metabolism in the absence of glycolytic activity. Furthermore, data suggesting that glucose can fuel fatty acid synthesis to support increased FAO in alternatively activated macrophages provides a link between glycolysis, fatty acid synthesis, and FAO.…”