Figure 1.

Macrophage metabolism and functional activation. Inflammatory activation: on exposure to stimuli like lipopolysaccharide (LPS) or interferon γ (IFN-γ), macrophages mainly use glycolysis as a fast source of energy to support their proinflammatory functions. Acetyl-CoA has a multiple role, since it fuels a split tricarboxylic acid (TCA) cycle (with the production of metabolites sustaining inflammatory functions as itaconate and succinate) and the synthesis of fatty acids (FAs), building blocks for inflammatory mediators. In parallel, LPS stimulation can induce sterol regulatory element-binding protein 1 a (SREBP-1a) expression through nuclear factor kappa B (NF-κB) activity. SREBP-1a promotes several transcription programs, including those for components of NLRP3 inflammasome, fatty acid synthase (FASN) as well as other proinflammatory genes. Anti-inflammatory activation: on interleukin 4 (IL-4) stimulation, FAs intake increases and the transcription factor STAT6 is activated, with consequent promotion of peroxisome proliferator–activated receptors PPARδ and PPARγ expression. PPARδ can sense the increased influx of FAs and subsequently induce transcription of anti-inflammatory genes, while PPARγ mainly facilitates fatty acid oxidation (FAO). In the mitochondria, a complete TCA cycle occurs and fuels oxidative phosphorylation (OXPHOS) for energy production. This process can be supported also by products of glycolysis, which is induced at modest levels by the activity of mTORC1 and mTORC2 after IL-4 stimulation.