Itaconate: the poster child of metabolic reprogramming in macrophage function

Abstract

Itaconate is one of the best examples of the consequences of metabolic reprogramming during immunity. It is made by diverting aconitate away from the tricarboxylic acid cycle during inflammatory macrophage activation. The main reason macrophages exhibit this response currently appears to be for an anti-inflammatory effect, with itaconate connecting cell metabolism, oxidative and electrophilic stress responses and immune responses. A role for itaconate in the regulation of type I interferons during viral infection has also been described, as well as in M2 macrophage function under defined circumstances. Finally, macrophage-specific itaconate production has also been shown to have a pro-tumour effect. All of these studies point towards itaconate being a critical immunometabolite that could have far-reaching consequences for immunity, host defence and tumorigenesis.

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Fig. 1: Metabolic remodelling of activating macrophages.
Fig. 2: Itaconate and chemical mimetics.
Fig. 3: Itaconate modifies proteins to elicit an anti-inflammatory effect.
Fig. 4: The intersection between itaconate and type I interferons.
Fig. 5: Itaconate, M2 macrophages, tumour-associated macrophages and immune-paralysed monocytes.

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Acknowledgements

M.N.A. thanks his colleagues in the Department of Pathology and Immunology at the Washington University School of Medicine for guidance and advice.

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Nature Reviews Immunology thanks K. Hiller, T. Horng and other anonymous reviewer(s) for their contribution to the peer review of this work.

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L.A.J.O. and M.N.A. both wrote and edited the manuscript.

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Correspondence to Luke A. J. O’Neill or Maxim N. Artyomov.

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Glossary

Glycolysis

A metabolic pathway that generates the cellular high-energy store of ATP by oxidizing glucose to pyruvate. In eukaryotic cells, pyruvate is further oxidized in mitochondria into CO2 and H2O via the tricarboxylic acid cycle in a process known as ‘aerobic respiration’. This results in a net yield of 36–38 molecules of ATP per metabolized molecule of glucose.

Tricarboxylic acid cycle

(TCA cycle; also known as the Krebs cycle or citric acid cycle). This pathway catalyses the oxidation of acetyl-CoA (from glucose or fatty acids, or indirectly from amino acids) to generate NADH and FADH, which fuel the electron transport chain and thereby oxidative phosphorylation and ATP production. The TCA cycle also serves as a source of precursors for amino acid and lipid synthesis.

Anaplerotic cycle

A ‘broken’ metabolic cycle, occurring when there is no further continuous metabolic flux across the cycle and individual reactions are rendered inactive or incorporated into different pathways.

Hypoxia-inducible factor 1α

(HIF1α). A transcription factor that regulates the expression of many metabolic enzymes (especially in the glycolysis pathway) and inflammatory mediators such as IL-1β.

Reverse electron transport

A state of the electron transport chain when electrons are flowing in the opposite direction.

Oxidative stress

Cells continuously produce reactive oxygen species (ROS) such as hydrogen peroxide or superoxide anions. Under physiological conditions, mitochondria are the main source, and cellular antioxidants ensure that the redox equilibrium is maintained. During inflammatory responses, major cytosolic production of ROS and reactive nitric oxide species also contributes to creating oxidative stress.

Electrophilic stress response

(ESR). A cellular response to endogenous and exogenous metabolites and compounds that can serve as electrophiles (that is, compounds capable of accepting an electron pair (Michael acceptors)). Electrophiles are highly reactive to sulfhydryl groups in the cell.

M2 macrophages

‘M1’ and ‘M2’ are somewhat artificial classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Oxidative phosphorylation

The metabolic pathway that occurs at the inner mitochondrial membrane and uses an electrochemical gradient created by the oxidation of electron carriers to generate ATP.

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O’Neill, L.A.J., Artyomov, M.N. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol 19, 273–281 (2019). https://doi.org/10.1038/s41577-019-0128-5

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