Effects of Metabolism on Macrophage Polarization Under Different Disease Backgrounds

Abstract

Macrophages are versatile immune cells associated with various diseases, and their phenotypes and functions change on the basis of the surrounding environments. Reprogramming of metabolism is required for the proper polarization of macrophages. This review will focus on basic metabolic pathways, the effects of key enzymes and specific products, relationships between cellular metabolism and macrophage polarization in different diseases and the potential prospect of therapy targeted key metabolic enzymes. In particular, the types and characteristics of macrophages at the maternal-fetal interface and their effects on a successful conception will be discussed.

Keywords: macrophage; maternal-fetal interface; metabolism; polarization; pregnancy.

Figure 1

The common transcription factors and the differences of stimuli, markers, secreted cytokines, the main regulate pathways and functions between M1 and M2 macrophages. iNOS, inducible nitric oxide synthase; Arg1, Arginase 1; LPS, lipopolysaccharides; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN-γ, interferon-gamma; IL, interleukin; TNF-α, tumor necrosis factor-α; TGF‐β, transforming growth factor‐β; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; EGF, epidermal growth factor; Ym1, chitinase 3-like 3; Fizz1, resistin-like-α; MIP-1β, macrophages inflammatory protein; MCP-1, monocyte chemo-attractant protein-1; RANTES, regulated on activation, normal T cell expressed and secreted; ERK, extracellular signal-regulated kinase; RBP-J, recombination signal-binding protein Jk; IRF, interferon‐regulatory factors; NF‐κB, nuclear factor‐κB; AP1, activator protein1; AMPK, adenosine monophosphate kinase; PPAR‐γ, peroxisome proliferator‐activated receptor‐γ; SIRPα, signal regulatory protein α. RBP-J, recombination signal-binding protein Jk.

Figure 2

The main metabolic pathways and crucial metabolites in macrophages. Ru5P, d-ribulose-5-phosphate; Xu5P, d-xylulose-5-phosphate; RPE, ribulose 5-phosphate 3-epimerase; PPP, pentose phosphate pathway; TCA, tricarboxylic acid; FAS, fatty acid synthesis; FAO, fatty acid oxidation; Acetyl-CoA, acetyl-Coenzyme A; OXPHOS, oxidative phosphorylation; α-KG, α-ketoglutarate.

Figure 3

The main metabolic pathways in macrophages. In the cytosol, glucose is converted into L-lactate by glycolysis, in which HK, PFK1 and PK are key enzymes. In the progress of glycolysis, glucose-6-P can be shunted to PPP pathway sustaining pentose phosphates and NADPH production. Pentose phosphates are used for the synthesis of amnio acid and nucleotide, while NADPH contributes to the production of ROS and NO. Pyruvate is induced to lactate in hypoxic conditions, whereas decarboxylated into acetyl-CoA within the mitochondria in normoxic conditions. Here, acetyl-CoA enters into the TCA cycle, providing reducing agents to the ETC through OXPHOS to generate energy. Citrate, a metabolite in TCA, participates in fatty acid synthesis when exported to the cytoplasm. Acetyl-CoA produced from FAS can be transferred into mitochondria and take part in the FAO. In M1 macrophages, two breakpoints cause the production of itaconate and the accumulation of succinate that induces HIF-1α mediated upregulation of glycolysis and IL-1β production.What’s more, the production of NO inhibits ETC. M2 macrophages can obtain enough ATP from OXPHOS through the TCA cycle. As for energy gain, FAO is essential. HK, hexokinase; Glucose 6-P, glucose 6-phosphate; Fructose 6-P, fructose 6-phosphate; PFK1, 6-phosphofructokinase 1; PK, pyruvate kinase; PPP, pentose phosphate pathway; G6PD, glucose 6-phosphate dehydrogenase; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ETC, electron transport chain; TCA, tricarboxylic acid; OXPHOS, oxidative phosphorylation; IDH, isocitrate dehydrogenase; NADPH, nicotinamide-adenine dinucleotide phosphate; SDH, succinate dehydrogenase; FAS, fatty acid synthesis; FAO, fatty acid oxidation; Acetyl-CoA, acetyl-Coenzyme A; IL-1β, interleukin-1β; HIF-1α, hypoxia inducible factor 1α.