Metabolic reprogramming in macrophage responses

Abstract

Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.

Keywords: Fatty acid oxidation; Fatty acid synthesis; Glycolysis; Macrophages; Metabolism.

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

Fig. 2

Metabolic characteristics of M2/M [IL-4/IL-10] macrophages. (I) Arginine is metabolized by arginase to urea and ornithine, which participates in the synthesis of polyamines; (II) glycolytic activity is decreased, as M2 may selectively express PFKFB1, which has a low net activity to maintain higher F2,6BP concentrations that can promote PFK1 activity; (III) PPP activity is decreased because of CARKL upregulation; (IV) the TCA cycle is intact; (V) FAO pathway activity is enhanced; and (VI) glutamine metabolism is increased. Glutamine can contribute to replenishment of the TCA cycle and the production of UDP-GlcNAc, which promotes the glycosylation of lectin/mannose receptors—among the most typical M2 polarization markers. In addition, GS is expressed in M2 macrophages and plays a positive role in M2 (IL-10) polarization. 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; α-KG, α-ketoglutarate; CARKL, carbohydrate kinase-like protein; PKM2, pyruvate kinase; PFK1, phosphofructokinase1; PDH, pyruvate dehydrogenase; CPT, carnitine palmitoyltransferase; FA, fatty acid; LAL, lysosomal acid lipase; GLS, glutaminase; GS, glutamine synthetase; Arg1, arginase 1