Skip to main content
. 2017 Jan 31;8:61. doi: 10.3389/fimmu.2017.00061

Figure 1.

Figure 1

Metabolic control of macrophage activation. (A,B) Metabolic signaling pathways are activated by polarizing signals to coordinate metabolic support of macrophage activation. Akt is activated by TBK/IKKe in LPS-stimulated dendritic cells (A), while IL-4R signaling impinges on PI3K to activate mTORC2, Akt, and mTORC1 in M(IL-4) macrophages (B). One consequence of LPS-mediated Akt activation is increased glucose oxidation. This supports production of phospholipids, which allows for expansion of the secretory compartment for elaboration of high levels of proinflammatory cytokines (A). In M(IL-4) macrophages, one consequence of Akt–mTORC1 activation is to increase Acly expression and activity. This enhances production of a cytosolic/nuclear pool of Ac-CoA, which regulates histone acetylation at a subset of IL-4-inducible genes (B). Note that this figure illustrates what is currently known regarding the major metabolic targets of Akt and mTOR in their control of M(LPS) and M(IL-4) activation, and that additional targets will undoubtedly emerge in future studies. (C,D) Metabolic reprograming regulates macrophages activation and function. (C) M(LPS) activation is associated with increased aerobic glycolysis to generate high levels of lactate and associated with pentose phosphate pathway (PPP) activity to make NADPH and nucleotides. Citrate is used for Ac-CoA and phospholipid production to support increased cytokine secretion and also gives rise to the antimicrobial species itaconate. Downregulation of isocitrate dehydrogenase expression (1) and inhibition of succinate dehydrogenase by itaconate (2) disrupt the TCA cycle in M(LPS) macrophages, requiring glutaminolysis and the arginosuccinate shunt (not shown) to provide α-ketoglutarate (AKG) and fumarate (fum) to replenish the cycle. (D) M(IL-4) activation is associated with increased utilization of glucose, fatty acids, and glutamine. Glucose goes to support N-glycosylation through UDP-GlcNAc. Multiple carbon substrates, including glucose, fatty acids, and glutamine, drive increased TCA cycle activity to boost histone acetylation. β-Oxidation is fueled by fatty acids that are either imported or synthesized de novo from glucose. Succ, succinate; OAA, oxaloacetate.