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A guide to immunometabolism for immunologists

Key Points

  • Immunometabolism describes the changes that occur in intracellular metabolic pathways in immune cells during activation.

  • Six major pathways have been studied in immune cells in detail: glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism.

  • Glycolysis and fatty acid synthesis are key features of lipopolysaccharide (LPS)-activated macrophages; by contrast, interleukin-4 (IL-4)-activated macrophages mainly use oxidative phosphorylation and fatty acid oxidation to generate energy.

  • Effector T cells are highly glycolytic whereas memory T cells have an oxidative metabolism.

  • Metabolites, such as succinate and citrate, and enzymes, such as pyruvate kinase isoenzyme M2 (PKM2), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and enolase, have roles outside of metabolism that promote specific events during immune cell activation.

  • Small molecules can target metabolic pathways and alter the phenotype of immune cells, raising the possibility of therapeutic intervention

Abstract

In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.

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Figure 1: Metabolic reprogramming by the immune system.
Figure 2: Six major metabolic pathways.
Figure 3: Glycolysis and the pentose phosphate pathway in immunity.
Figure 4: The TCA cycle in macrophages.
Figure 5: Fatty acid synthesis and oxidation in immunity.
Figure 6: Amino acid metabolism in immunity.
Figure 7: Metabolism of immune cell subtypes.

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Acknowledgements

L.A.J.O. acknowledges Science Foundation Ireland, The European Research Council and The Wellcome Trust for research funding.

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PowerPoint slides

Glossary

Mechanistic target of rapamycin

(mTOR). An atypical serine/threonine kinase that is present in two distinct complexes. mTOR complex 1 (mTORC1), is composed of mTOR, Raptor, MLST8 (also known as GβL), PRAS40 and DEPTOR; it is inhibited by rapamycin.

Electron transport chain

The series of proteins in the inner mitochondrial membrane that transfer electrons in a series of redox reactions, leading to proton pumping across the membrane.

2-deoxyglucose

A derivative of glucose that inhibit hexokinase, thereby blocking the first step in glycolysis.

Aerobic glycolysis

Glycolysis occurring when oxygen is present.

Foam cells

Fat-laden macrophages commonly seen in the plaques occurring in atherosclerosis.

Futile cycle

Two metabolic pathways running in opposite directions that seem to cancel each other out metabolically.

Metabolic enzymes

Enzymes in metabolic pathways that convert substrates into products. Major classes are dehydrogenases (which remove hydrogen from a substrate in an oxidation–reduction reaction), isomerases (which convert a molecule from one isomer to another), synthases (which link two molecules together without using ATP as an energy source), carboxylases (which add a carboxyl group to a substrate) and kinases (which add a phosphate group to a molecule).

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O'Neill, L., Kishton, R. & Rathmell, J. A guide to immunometabolism for immunologists. Nat Rev Immunol 16, 553–565 (2016). https://doi.org/10.1038/nri.2016.70

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