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Immunometabolism in systemic lupus erythematosus

Key Points

  • In systemic lupus erythematous (SLE), CD4+ T cells have a hypermetabolic state dominated by oxidation, mitochondrial abnormalities, activation of mTORC1 and increased glucose flux

  • Targeting T cell metabolism has therapeutic effects in mouse models of lupus and in the T cells of patients with SLE

  • Cell-specific metabolic imbalances probably also affect other immune cells in SLE, including neutrophils, plasma cells and macrophages, and specific metabolic targeting of these cells could have therapeutic benefit

  • A better understanding of the complexities of immunometabolism in SLE could lead to personalized therapeutic options

  • The metabolome, potentially intersecting with the microbiota, might provide biomarkers for SLE

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by pathogenic autoantibodies directed against nucleoprotein complexes. Beyond the activation of autoreactive B cells, this process involves dysregulation in many other types of immune cells, including CD4+ T cells, dendritic cells, macrophages and neutrophils. Metabolic substrate utilization and integration of cues from energy sensors are critical checkpoints of effector functions in the immune system, with common as well as cell-specific programmes. Patients with SLE and lupus-prone mice present with activated metabolism of CD4+ T cells, and the use of metabolic inhibitors to normalize these features is associated with therapeutic effects. Far less is known about the metabolic requirements of B cells and myeloid cells in SLE. This article reviews current knowledge of the alterations in metabolism of immune cells in patients with SLE and mouse models of lupus in the context of what is known about the metabolic regulation of these cells during normal immune responses. How these alterations might contribute to lupus pathogenesis and how they can be targeted therapeutically are also discussed.

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Figure 1: Metabolic activation of CD4+ T cells in SLE.
Figure 2: Potential metabolic pathways involved in B cells in SLE.
Figure 3: Gut microbial metabolites and immune dysregulation in SLE.

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Acknowledgements

The author's work is supported by Alliance for Lupus Research Target Identification in Lupus grants (TIL 85521 and TIL 75018).

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Correspondence to Laurence Morel.

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Glossary

Electron transport chain

A series of proteins in the inner mitochondrial membrane that transfer electrons from one to the other in a series of redox reactions, resulting in the movement of protons out of the mitochondrial matrix and in the synthesis of ATP.

Oxidative phosphorylation

A metabolic pathway that produces ATP from the oxidation of acetyl-CoA and the transfer of electrons to the electron transport chain via NADH and FADH2.

Aeorbic glycolysis

(Also known as the 'Warburg effect') The abrupt metabolic switch from oxidative phosphorylation to glycolysis, regardless of the availability of oxygen, to provide energy for cell proliferation and effector functions.

Glycolysis

An oxygen-independent metabolic pathway that generates two molecules of pyruvate, ATP and NADH from every one molecule of glucose, supporting the tricarboxylic acid cycle and providing intermediates for the pentose phosphate pathway, glycosylation reactions and for the synthesis of biomolecules (including serine, glycine, alanine and acetyl-CoA).

Pentose phosphate pathway (PPP)

An anabolic metabolic pathway parallel to glycolysis that branches out from glycolysis with the conversion of glucose-6-phosphate to ribose 5-phosphate and generates the reducing equivalents NADPH, ribose 5-phosphate (used in the synthesis of nucleotides and nucleic acids) and erythrose-4-phosphosphate (used in the synthesis of amino acids).

Lipid rafts

Microdomains of the plasma membrane that are enriched in cholesterol and glycosphingolipids and serve as self-organizing centres for the assembly of signalling molecules.

Statins

A class of lipid-lowering drugs that inhibit a key enzyme in the synthesis of cholesterol, HMG-CoA reductase.

Fatty acid oxidation

A metabolic process that produces ATP from the oxidation of acetyl-CoA derived from the mobilization of fatty acids.

Tricarboxylic acid (TCA) cycle

(Also known as the Krebs cycle) A set of connected pathways in the mitochondrial matrix, which metabolize acetyl-CoA derived from glycolysis or fatty acid oxidation, producing NADH and FADH2 for the electron transport chain and precursors for amino acid and fatty acid synthesis.

NETosis

A specialized form of cell death characterized by the release of neutrophil extracellular traps (NETs), which are chromatin structures loaded with granular and nucleic proteins.

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Morel, L. Immunometabolism in systemic lupus erythematosus. Nat Rev Rheumatol 13, 280–290 (2017). https://doi.org/10.1038/nrrheum.2017.43

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