Fig. 1

Metabolic characteristics of M1/M [LPS(±IFN-γ)] macrophages. (I) Arginine is metabolized by iNOS to citrulline and NO. Citrulline can be used with aspartate, as catalyzed by Ass1, to generate argininosuccinate, which is further catalyzed by Asl to arginine and fumarate; (II) glycolytic activity is enhanced; (III) PPP activity is increased, generating NADPH for ROS and NO production by NAPDH oxidase and iNOS, respectively; and (IV) citrate accumulates and is then exported into the cytoplasm via CIC and transformed into acetyl-CoA and oxaloacetate via ACLY. Acetyl-CoA is used for FAS and protein acetylation. Oxaloacetate is further metabolized to pyruvate, accompanied by NADPH and NO production. Citrate also generates itaconate via IRG1, thus inhibiting SDH and causing the second break in the TCA cycle. (VI) Succinate accumulates via inhibition of SDH (VII) and derivation from glutamine through anaplerosis via αKG and the GABA shunt pathway. Succinate can stabilize HIF1α, leading to the release of IL-1β. (VIII) The high mitochondrial membrane potential induced by LPS leads to reversal of the normal direction of electron flux through complex III, causing RET in complex I and driving ROS production. Succinate can also be released into the extracellular milieu, where it is sensed by GPR91 to promote inflammatory responses. GLUT, glucose transporter; HK, hexokinase; G6P, glucose-6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose-1,6-bisphosphate; F2,6BP, fructose-2,6-bisphosphate; RU5P, ribulose-5-phosphate; PKM2, pyruvate kinase; PFK1, phosphofructokinase1; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; iNOS, inducible nitric oxide synthase; MDH, malate dehydrogenase; αKG, α-ketoglutarate; ASS, argininosuccinate synthase; ASL, isocitrate dehydrogenase; RET, reverse electron transport; IRG1, immunoresponsive gene 1; IDH, isocitrate dehydrogenase; ACO2, aconitase 2; CARKL, carbohydrate kinase-like protein; ACLY, ATP-citrate lyase; SDH, succinate dehydrogenase; CIC, citrate carrier