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Immunometabolism in early and late stages of rheumatoid arthritis

Nature Reviews Rheumatology volume 13, pages 291–301 (2017)Cite this article

Subjects

Key Points

  • A fundamental abnormality in rheumatoid arthritis (RA) is the inappropriate growth of immune cells and stromal cells, imposing high metabolic demands to generate energy and biosynthetic precursors

  • In RA, immune cells and stromal cells undergo metabolic adaptations to generate biomass

  • The disease process in RA involves several stages and multiple tissue sites (such as lymphoid organs and joints), each with a distinct metabolic environment

  • A metabolic signature associated with RA involves the dampening of glycolytic flux and the shunting of glucose into the pentose phosphate pathway in CD4+ T cells

  • In the rheumatoid joint, metabolic intermediates function as signalling molecules and facilitate cell–cell communication, amplifying inflammatory tissue damage

  • The dependence of the rheumatoid disease process on metabolic activity identifies metabolic interference as a potential therapeutic strategy

Abstract

One of the fundamental traits of immune cells in rheumatoid arthritis (RA) is their ability to proliferate, a property shared with the joint-resident cells that form the synovial pannus. The building of biomass imposes high demands for energy and biosynthetic precursors, implicating metabolic control as a basic disease mechanism. During preclinical RA, when autoreactive T cells expand and immunological tolerance is broken, the main sites of disease are the secondary lymphoid tissues. Naive CD4+ T cells from patients with RA have a distinct metabolic signature, characterized by dampened glycolysis, low ATP levels and enhanced shunting of glucose into the pentose phosphate pathway. Equipped with high levels of NADPH and depleted of intracellular reactive oxygen species, such T cells hyperproliferate and acquire proinflammatory effector functions. During clinical RA, immune cells coexist with stromal cells in the acidic milieu of the inflamed joint. This microenvironment is rich in metabolic intermediates that are released into the extracellular space to shape cell–cell communication and the functional activity of tissue-resident cells. Increasing awareness of how metabolites regulate signalling pathways, guide post-translational modifications and condition the tissue microenvironment will help to connect environmental factors with the pathogenic behaviour of T cells in RA.

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Figure 1: Lymphocytes during the disease process of rheumatoid arthritis in different tissue environments.
Figure 2: Emerging hallmarks of T cells in rheumatoid arthritis.
Figure 3: Glucose shunting into the pentose phosphate pathway in T cells in rheumatoid arthritis.
Figure 4: Metabolic intermediates in the rheumatoid joint.

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Acknowledgements

The work of the authors was supported by grants from the NIH (R01 AR042527, R01 HL 117913, R01 AI108906 and P01 HL129941 to C.M.W. and R01 AI108891, R01 AG045779, U19 AI057266, and I01 BX001669 to J.J.G.).

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  1. Department of Medicine, Stanford University School of Medicine, 269 Campus Drive West, Stanford, 94305, California, USA

    Cornelia M. Weyand & Jörg J. Goronzy

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  1. Cornelia M. Weyand
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  2. Jörg J. Goronzy
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Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Cornelia M. Weyand.

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Glossary

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 the synthesis of biomolecules (including serine, glycine, alanine and acetyl-CoA).

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.

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.

Hexosamine biosynthesis pathway

A side branch of glycolysis used to synthesize nucleotide sugars from fructose-6-phosphate and glutamine, such as uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which functions as a glycosyl donor for the posttranslational modification of biomolecules.

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 equivalent NADPH, ribose-5-phosphate (used in the synthesis of nucleotides and nucleic acids) and erythrose-4-phosphosphate (used in the synthesis of amino acids).

Warburg effect

The high utilization of glycolysis by rapidly proliferating cells and the subsequent release of lactate into the extracellular milieu; a phenomenon first desribed by Otto Warburg.

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Weyand, C., Goronzy, J. Immunometabolism in early and late stages of rheumatoid arthritis. Nat Rev Rheumatol 13, 291–301 (2017). https://doi.org/10.1038/nrrheum.2017.49

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