Figure 3 Metabolic configurations of M1 and M2 macrophages Figure 3 | Metabolic configurations of M1 and M2 macrophages. a | Classically activated M1 macrophages primarily use aerobic glycolysis to generate energy and molecules for biosynthetic processes, thereby increasing flux through the pentose phosphate pathway (PPP), leading to an increase in NADPH (an energy substrate for redox homeostasis and for the production of reactive oxygen species (ROS) by NADPH oxidases). ROS are also produced by mitochondria. Although the tricarboxylic acid (TCA) cycle is mainly fuelled by pyruvate from glycolysis and acetyl-CoA or succinyl-CoA from fatty acid oxidation, TCA intermediates removed from the mitochondria for use in biosynthetic pathways have to be replenished by glutamine in M1 macrophages due to the interruption of the TCA cycle at two positions. The first break in the TCA cycle leads to the accumulation of citrate, a substrate for the synthesis of itaconic acid and fatty acids (including the generation of prostaglandins). Anabolic synthesis of fatty acids generates NADPH and, subsequently, ROS via NADPH oxidases. The second break leads to the accumulation of succinate, which activates hypoxia-inducible factor 1α-induced inflammatory gene expression and increases glycolysis. The argininosuccinate shunt replenishes levels of fumarate and malate, required for citrate production, thereby generating nitric oxide (NO), which inhibits succinate dehydrogenase activity. b | Alternatively activated M2 macrophages are characterized by increased fatty acid oxidation, low glycolysis activity and reduced flux through the PPP. Acetyl-CoA generated by fatty acid oxidation enters the intact TCA cycle for oxidative metabolism. Glutamine is mainly used for the synthesis of amino-sugars and nucleotide sugars, but also fuels the TCA cycle. ETC, electron transport chain; GLUT1, glucose transporter type 1. Gaber, T. et al. (2017) Metabolic regulation of inflammation Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2017.37