Endogenous drivers of altered immune cell metabolism

Abstract

Dysregulated metabolism has long been recognized as a feature of many metabolic disorders. However, recent studies demonstrating that metabolic reprogramming occurs in immune cells have led to a growing interest in the relationship between metabolic rewiring and immune-mediated disease pathogeneses. It is clear now that immune cell subsets engage in different metabolic pathways depending on their activation and/or maturation state. As a result, it may be possible to modulate metabolic reprogramming for clinical benefit. In this review, we provide an overview of immune cell metabolism with focus on endogenous drivers of metabolic reprogramming given their link to a number of immune-mediated disorders.

Keywords: Immunometabolism; cellular respiration; damage or disease-associated molecular patterns; metabolic reprogramming.

Figure 1.

Cellular respiration and fatty acid metabolism. Cells engage a range of metabolic pathways depending on their needs. During glycolysis, glucose is first phosphorylated by hexokinase 2 (HK2) to generate glucose-6-phosphate (glucose-6P). Glucose-6P is isomerized to fructose-6-phosphate (fructose-6P), which is converted to fructose-1,6-biphosphate (fructose-1,6-biP) by phosphofructokinase (PFK). This is split into two: dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GA3P). GA3P continues through the remaining steps of glycolysis and is finally converted to pyruvate by pyruvate kinase (PK). Pyruvate can be exported from the cell as lactate under anaerobic conditions. In the presence of oxygen, pyruvate is converted to acetyl-CoA which enters the TCA cycle. NADH from the TCA cycle passes into the electron transport chain, completing oxidative phosphorylation and generating energy through a proton gradient. Acetyl-CoA can then enter the fatty acid synthesis pathway, where it is carboxylated by acetyl-CoA carboxylase (ACC) to form malonyl-CoA. Malonyl-CoA then passes through the remaining steps of this pathway, which are catalyzed by fatty acid synthases (FASN) resulting in 16-carbon palmitic acid. The fatty acid synthesis pathway is activated by mTORC1. mTORC1 is also responsible for the activation of HIF1α, which in turn can activate glycolysis by upregulating GLUT1 and HK2. Inhibition of fatty acid synthesis by AMPK results in activation of the fatty acid oxidation pathway, by lifting the inhibition placed on the enzyme carnitine palmitoyltransferase 1 (CPT1). Fatty acids first enter the cell and are converted to acyl-CoA, which then enters the carnitine shuttle to translocate into the mitochondria. Acyl-CoA then continues through the fatty acid oxidation pathway, generating acetyl-CoA, which can then enter the TCA cycle. (A color version of this figure is available in the online journal.)

Figure 2.

Major metabolic pathways engaged in immune cells. The metabolic pathways engaged by an immune cell depend on its activation state, maturation state, or specific effector subset. The pathways shown in red: glycolysis, fatty acid synthesis, amino acid metabolism, and the pentose phosphate pathway (PPP) are generally associated with activated and effector immune cells. Some examples of these cells include pro-inflammatory macrophages, activated DC, and specific effector T cell subsets. The pathways shown in green: TCA cycle and the electron transport chain (together comprising oxidative phosphorylation) and fatty acid oxidation are generally associated with naive, immature, or regulatory immune cells. Some examples of these cells include alternatively activated macrophages, immature DC, and naïve or regulatory T cells (Tregs). (A color version of this figure is available in the online journal.)