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Redox regulation of immunometabolism

Abstract

Metabolic pathways and redox reactions are at the core of life. In the past decade(s), numerous discoveries have shed light on how metabolic pathways determine the cellular fate and function of lymphoid and myeloid cells, giving rise to an area of research referred to as immunometabolism. Upon activation, however, immune cells not only engage specific metabolic pathways but also rearrange their oxidation–reduction (redox) system, which in turn supports metabolic reprogramming. In fact, studies addressing the redox metabolism of immune cells are an emerging field in immunology. Here, we summarize recent insights revealing the role of reactive oxygen species (ROS) and the differential requirement of the main cellular antioxidant pathways, including the components of the thioredoxin (TRX) and glutathione (GSH) pathways, as well as their transcriptional regulator NF-E2-related factor 2 (NRF2), for proliferation, survival and function of T cells, B cells and macrophages.

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Fig. 1: The redox metabolism of T cells.
Fig. 2: The redox metabolism of B cells.
Fig. 3: The redox metabolism of inflammatory M1 macrophages.

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Acknowledgements

The authors thank P. Nielsen for comments and advice on the manuscript. This work was supported by research grants from ETH Zurich (ETH-23-16-2) and SNF (310030B_182829).

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Correspondence to Jonathan Muri or Manfred Kopf.

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Glossary

Redox homeostasis

(Also known as redox balance). The condition by which cellular antioxidants balance reactive oxygen species (ROS) generation and elimination.

Anaplerotic conversion

(Also known as anaplerosis). The act of diversion of metabolites to the tricarboxylic acid (TCA) cycle aimed at replenishing TCA intermediates that have been extracted for biosynthesis.

Ferroptosis

An iron-dependent and reactive oxygen species (ROS)-mediated form of cell death induced by the accumulation of lipid peroxides. It is morphologically and biochemically distinct from apoptosis, necroptosis and pyroptosis.

M1 macrophages

(Classically activated macrophages). Pro-inflammatory macrophages induced by stimulation with lipopolysaccharide (LPS) and interferon-γ (IFNγ). They are known to play a positive role in immune responses against microbial pathogens and tumours through the phagocytosis of microbes, the production of pro-inflammatory cytokines and the initiation of the immune response.

M2 macrophages

(Alternatively activated macrophages). Anti-inflammatory macrophages induced by IL-4 and/or IL-13. They are involved in tissue repair upon damage and homeostasis of adipose tissue.

Inflammasomes

Cytosolic multiprotein complexes that activate the inflammatory caspase 1 in response to pathogenic microorganisms and sterile stressors, leading to the proteolytic maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, as well as to the cleavage of the pyroptosis executer gasdermin-D (GSDMD).

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Muri, J., Kopf, M. Redox regulation of immunometabolism. Nat Rev Immunol 21, 363–381 (2021). https://doi.org/10.1038/s41577-020-00478-8

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