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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).
Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).
Buck, M. D., O’Sullivan, D. & Pearce, E. L. T cell metabolism drives immunity. J. Exp. Med. 212, 1345–1360 (2015).
O’Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).
Boothby, M. & Rickert, R. C. Metabolic regulation of the immune humoral response. Immunity 46, 743–755 (2017).
Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).
Arner, E. S. Focus on mammalian thioredoxin reductases — important selenoproteins with versatile functions. Biochim. Biophys. Acta 1790, 495–526 (2009).
Brigelius-Flohe, R. & Maiorino, M. Glutathione peroxidases. Biochim. Biophys. Acta 1830, 3289–3303 (2013).
Kalinina, E. V., Chernov, N. N. & Novichkova, M. D. Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochemistry 79, 1562–1583 (2014).
Ceriello, A. & Motz, E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler. Thromb. Vasc. Biol. 24, 816–823 (2004).
Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).
Toyokuni, S., Okamoto, K., Yodoi, J. & Hiai, H. Persistent oxidative stress in cancer. FEBS Lett. 358, 1–3 (1995).
Andreadis, A. A., Hazen, S. L., Comhair, S. A. & Erzurum, S. C. Oxidative and nitrosative events in asthma. Free Radic. Biol. Med. 35, 213–225 (2003).
Jenner, P. Oxidative stress in Parkinson’s disease. Ann. Neurol. 53, S26–S38 (2003).
Lyras, L., Cairns, N. J., Jenner, A., Jenner, P. & Halliwell, B. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J. Neurochem. 68, 2061–2069 (1997).
Meischl, C. & Roos, D. The molecular basis of chronic granulomatous disease. Springer Semin. Immunopathol. 19, 417–434 (1998).
Lambeth, J. D. NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189 (2004).
Panday, A., Sahoo, M. K., Osorio, D. & Batra, S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol. Immunol. 12, 5–23 (2015).
Barua, S., Kim, J. Y., Yenari, M. A. & Lee, J. E. The role of NOX inhibitors in neurodegenerative diseases. IBRO Rep. 7, 59–69 (2019).
Ray, P. D., Huang, B. W. & Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 24, 981–990 (2012).
Fox, C. J., Hammerman, P. S. & Thompson, C. B. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844–852 (2005).
van der Windt, G. J. & Pearce, E. L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 249, 27–42 (2012).
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Gubser, P. M. et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).
Finlay, D. K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).
Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).
Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).
Macintyre, A. N. & Rathmell, J. C. Activated lymphocytes as a metabolic model for carcinogenesis. Cancer Metab. 1, 5 (2013).
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).
Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011). This paper demonstrates that activated T cells reprogramme their metabolism towards enhanced glycolytic, pentose phosphate and glutaminolytic pathways.
Patra, K. C. & Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 39, 347–354 (2014).
Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).
Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).
Hukelmann, J. L. et al. The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17, 104–112 (2016).
Macintyre, A. N. et al. Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34, 224–236 (2011).
Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489–499 (2013).
Endo, Y. et al. Obesity drives TH17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 12, 1042–1055 (2015).
Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).
van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).
van der Windt, G. J. et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl Acad. Sci. USA 110, 14336–14341 (2013).
O’Sullivan, D. et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75–88 (2014).
Ma, R. et al. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. Nat. Cell Biol. 20, 21–27 (2018).
Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).
Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227–232 (2013).
Holmgren, A. & Sengupta, R. The use of thiols by ribonucleotide reductase. Free Radic. Biol. Med. 49, 1617–1628 (2010).
Muri, J. et al. The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation. Nat. Commun. 9, 1851 (2018). This study demonstrates a key role for the TRX1 system in dNTP biosynthesis in the last step of the PPP during rapid T cell proliferation.
Muri, J. et al. The thioredoxin-1 and glutathione/glutaredoxin-1 systems redundantly fuel murine B-cell development and responses. Eur. J. Immunol. 49, 709–723 (2019).
Tagaya, Y. et al. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 8, 757–764 (1989).
Tagaya, Y. et al. IL-2 receptor(p55)/Tac-inducing factor. Purification and characterization of adult T cell leukemia-derived factor. J. Immunol. 140, 2614–2620 (1988).
Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).
Chakraborty, P. et al. Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells. J. Biol. Chem. 294, 9198–9212 (2019).
Levring, T. B. et al. Human CD4+ T cells require exogenous cystine for glutathione and DNA synthesis. Oncotarget 6, 21853–21864 (2015).
Geisberger, R. et al. B- and T-cell-specific inactivation of thioredoxin reductase 2 does not impair lymphocyte development and maintenance. Biol. Chem. 388, 1083–1090 (2007).
Conrad, M. et al. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol. Cell Biol. 24, 9414–9423 (2004).
Hwang, J. et al. The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein. Nat. Commun. 5, 2958 (2014).
Muri, J., Thut, H. & Kopf, M. The thioredoxin-1 inhibitor Txnip restrains effector T-cell and germinal center B-cell expansion. Eur. J. Immunol. https://doi.org/10.1002/eji.202048851 (2020).
Wilde, B. R. & Ayer, D. E. Interactions between Myc and MondoA transcription factors in metabolism and tumourigenesis. Br. J. Cancer 113, 1529–1533 (2015).
Wu, N. et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49, 1167–1175 (2013).
Kaadige, M. R., Looper, R. E., Kamalanaadhan, S. & Ayer, D. E. Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. Proc. Natl Acad. Sci. USA 106, 14878–14883 (2009).
Oka, S. et al. Thioredoxin binding protein-2/thioredoxin-interacting protein is a critical regulator of insulin secretion and peroxisome proliferator-activated receptor function. Endocrinology 150, 1225–1234 (2009).
Cha-Molstad, H., Saxena, G., Chen, J. & Shalev, A. Glucose-stimulated expression of Txnip is mediated by carbohydrate response element-binding protein, p300, and histone H4 acetylation in pancreatic β cells. J. Biol. Chem. 284, 16898–16905 (2009).
Stoltzman, C. A. et al. Glucose sensing by MondoA:Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression. Proc. Natl Acad. Sci. USA 105, 6912–6917 (2008).
Patwari, P. et al. Thioredoxin-independent regulation of metabolism by the α-arrestin proteins. J. Biol. Chem. 284, 24996–25003 (2009).
Yu, F. X., Chai, T. F., He, H., Hagen, T. & Luo, Y. Thioredoxin-interacting protein (Txnip) gene expression: sensing oxidative phosphorylation status and glycolytic rate. J. Biol. Chem. 285, 25822–25830 (2010).
Klein Geltink, R. I. et al. Mitochondrial priming by CD28. Cell 171, 385–397 (2017). This paper shows that TXNIP downregulation ensures mitochondrial priming and future protective memory T cell responses.
Saetre, R. & Rabenstein, D. L. Determination of cysteine in plasma and urine and homocysteine in plasma by high-pressure liquid chromatography. Anal. Biochem. 90, 684–692 (1978).
Lo, M., Wang, Y. Z. & Gout, P. W. The Xc– cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J. Cell Physiol. 215, 593–602 (2008).
Garg, S. K., Yan, Z., Vitvitsky, V. & Banerjee, R. Differential dependence on cysteine from transsulfuration versus transport during T cell activation. Antioxid. Redox Signal. 15, 39–47 (2011).
Angelini, G. et al. Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc. Natl Acad. Sci. USA 99, 1491–1496 (2002).
Yan, Z. & Banerjee, R. Redox remodeling as an immunoregulatory strategy. Biochemistry 49, 1059–1066 (2010).
Castellani, P., Angelini, G., Delfino, L., Matucci, A. & Rubartelli, A. The thiol redox state of lymphoid organs is modified by immunization: role of different immune cell populations. Eur. J. Immunol. 38, 2419–2425 (2008).
Arensman, M. D. et al. Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity. Proc. Natl Acad. Sci. USA 116, 9533–9542 (2019).
Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692–705 (2014).
Sinclair, L. V. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500–508 (2013).
Pollizzi, K. N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).
Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).
Carr, E. L. et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185, 1037–1044 (2010).
Araujo, L., Khim, P., Mkhikian, H., Mortales, C. L. & Demetriou, M. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife 6, e21330 (2017).
Blagih, J. et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42, 41–54 (2015).
Tompkins, S. C. et al. Disrupting mitochondrial pyruvate uptake directs glutamine into the TCA cycle away from glutathione synthesis and impairs hepatocellular tumorigenesis. Cell Rep. 28, 2608–2619.e6 (2019).
Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013). This pioneering study shows that mitochondrial ROS are required for T cell-mediated immunity.
Yi, J. S., Holbrook, B. C., Michalek, R. D., Laniewski, N. G. & Grayson, J. M. Electron transport complex I is required for CD8+ T cell function. J. Immunol. 177, 852–862 (2006).
Mak, T. W. et al. Glutathione primes T cell metabolism for inflammation. Immunity 46, 675–689 (2017). This paper dissects the mechanisms whereby glutathione buffers ROS to allow metabolic rewiring during inflammatory T cell responses.
Lian, G. et al. Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. eLife 7, e36158 (2018).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).
Klein-Hessling, S. et al. NFATc1 controls the cytotoxicity of CD8+ T cells. Nat. Commun. 8, 511 (2017).
Vaeth, M. et al. Store-operated Ca2+ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity 47, 664–679.e6 (2017).
Namgaladze, D., Hofer, H. W. & Ullrich, V. Redox control of calcineurin by targeting the binuclear Fe2+–Zn2+ center at the enzyme active site. J. Biol. Chem. 277, 5962–5969 (2002).
Kurniawan, H. et al. Glutathione restricts serine metabolism to preserve regulatory T cell function. Cell Metab. 31, 920–936.e7 (2020). This works describes the role of GSH in restricting serine availability to preserve the functionality of regulatory T cells.
Pollizzi, K. N. & Powell, J. D. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14, 435–446 (2014).
Rolf, J. et al. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 43, 889–896 (2013).
Case, A. J. et al. Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge. Free Radic. Biol. Med. 50, 448–458 (2011).
Tse, H. M. et al. NADPH oxidase deficiency regulates TH lineage commitment and modulates autoimmunity. J. Immunol. 185, 5247–5258 (2010).
Jackson, S. H., Devadas, S., Kwon, J., Pinto, L. A. & Williams, M. S. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 5, 818–827 (2004). This study reports that mature T cells express a NADPH oxidase that generates ROS and thus regulates elements of TCR signalling.
Kaminski, M. M. et al. T cell activation is driven by an ADP-dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation. Cell Rep. 2, 1300–1315 (2012).
Kaminski, M. M. et al. Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J. Immunol. 184, 4827–4841 (2010).
Laniewski, N. G. & Grayson, J. M. Antioxidant treatment reduces expansion and contraction of antigen-specific CD8+ T cells during primary but not secondary viral infection. J. Virol. 78, 11246–11257 (2004).
Schreck, R., Rieber, P. & Baeuerle, P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J. 10, 2247–2258 (1991).
Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. USA 104, 14418–14423 (2007).
Phan, A. T. & Goldrath, A. W. Hypoxia-inducible factors regulate T cell metabolism and function. Mol. Immunol. 68, 527–535 (2015).
Previte, D. M. et al. Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLoS ONE 12, e0175549 (2017).
Franchina, D. G., Dostert, C. & Brenner, D. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol. 39, 489–502 (2018).
Lillig, C. H., Berndt, C. & Holmgren, A. Glutaredoxin systems. Biochim. Biophys. Acta 1780, 1304–1317 (2008).
Lillig, C. H. & Holmgren, A. Thioredoxin and related molecules — from biology to health and disease. Antioxid. Redox Signal. 9, 25–47 (2007).
Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015). This work provides evidence that GPX4 prevents lipid peroxidation-driven ferroptosis in activated T cells.
Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).
Cronin, S. J. F. et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563, 564–568 (2018).
Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013).
Lee, D. H. et al. Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation. Cell Death Dis. 7, e2208 (2016).
Won, H. Y. et al. Glutathione peroxidase 1 deficiency attenuates allergen-induced airway inflammation by suppressing TH2 and TH17 cell development. Antioxid. Redox Signal. 13, 575–587 (2010).
Taguchi, K., Motohashi, H. & Yamamoto, M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cell 16, 123–140 (2011).
Morzadec, C. et al. Nrf2 expression and activity in human T lymphocytes: stimulation by T cell receptor activation and priming by inorganic arsenic and tert-butylhydroquinone. Free Radic. Biol. Med. 71, 133–145 (2014).
Turley, A. E., Zagorski, J. W. & Rockwell, C. E. The Nrf2 activator tBHQ inhibits T cell activation of primary human CD4 T cells. Cytokine 71, 289–295 (2015).
Zagorski, J. W. et al. The Nrf2 activator, tBHQ, differentially affects early events following stimulation of Jurkat cells. Toxicol. Sci. 136, 63–71 (2013).
Rangasamy, T. et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J. Exp. Med. 202, 47–59 (2005).
Rockwell, C. E., Zhang, M., Fields, P. E. & Klaassen, C. D. TH2 skewing by activation of Nrf2 in CD4+ T cells. J. Immunol. 188, 1630–1637 (2012).
Suzuki, T. et al. Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice. Mol. Cell Biol. 37 (2017).
Noel, S. et al. T lymphocyte-specific activation of Nrf2 protects from AKI. J. Am. Soc. Nephrol. 26, 2989–3000 (2015).
Maj, T. et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18, 1332–1341 (2017).
Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).
Hayes, J. D. & Dinkova-Kostova, A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199–218 (2014).
Jellusova, J. Cross-talk between signal transduction and metabolism in B cells. Immunol. Lett. 201, 1–13 (2018).
Jellusova, J. The role of metabolic checkpoint regulators in B cell survival and transformation. Immunol. Rev. 295, 39–53 (2020).
Akkaya, M. & Pierce, S. K. From zero to sixty and back to zero again: the metabolic life of B cells. Curr. Opin. Immunol. 57, 1–7 (2019).
Li, C. et al. Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma. Oncotarget 3, 314–326 (2012).
Fiskus, W. et al. Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res. 74, 2520–2532 (2014).
Wang, J. et al. Repurposing auranofin to treat TP53-mutated or PTEN-deleted refractory B-cell lymphoma. Blood Cancer J. 9, 95 (2019).
Fidyt, K. et al. Targeting the thioredoxin system as a novel strategy against B-cell acute lymphoblastic leukemia. Mol. Oncol. 13, 1180–1195 (2019).
Harris, I. S. et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).
Kiebala, M. et al. Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach. Exp. Hematol. 43, 89–99 (2015).
Chan, L. N. et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479–483 (2017). This report highlights the key role of TXNIP in performing metabolic gatekeeper functions by suppression of glucose uptake.
Cobaleda, C., Schebesta, A., Delogu, A. & Busslinger, M. Pax5: the guardian of B cell identity and function. Nat. Immunol. 8, 463–470 (2007).
Bertolotti, M., Sitia, R. & Rubartelli, A. On the redox control of B lymphocyte differentiation and function. Antioxid. Redox Signal. 16, 1139–1149 (2012).
Vene, R. et al. Redox remodeling allows and controls B-cell activation and differentiation. Antioxid. Redox Signal. 13, 1145–1155 (2010).
Waters, L. R., Ahsan, F. M., Wolf, D. M., Shirihai, O. & Teitell, M. A. Initial B cell activation induces metabolic reprogramming and mitochondrial remodeling. iScience 5, 99–109 (2018).
Muri, J., Thut, H., Bornkamm, G. W. & Kopf, M. B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. Cell Rep. 29, 2731–2744 e2734 (2019). This study shows that GPX4 detoxifies lipid peroxides and prevents ferroptosis in B1 cells and marginal zone B cells but not in follicular B cells.
Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).
Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).
Bertolotti, M. et al. B- to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses. Antioxid. Redox Signal. 13, 1133–1144 (2010).
Aronov, M. & Tirosh, B. Metabolic control of plasma cell differentiation — what we know and what we don’t know. J. Clin. Immunol. 36, 12–17 (2016).
Dufort, F. J. et al. Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for ATP–citrate lyase in lipopolysaccharide-induced differentiation. J. Biol. Chem. 289, 7011–7024 (2014).
Lam, W. Y. et al. Mitochondrial pyruvate import promotes long-term survival of antibody-secreting plasma cells. Immunity 45, 60–73 (2016).
Jang, K. J. et al. Mitochondrial function provides instructive signals for activation-induced B-cell fates. Nat. Commun. 6, 6750 (2015).
Singh, D. K. et al. The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 121, 281–293 (2005).
Wheeler, M. L. & Defranco, A. L. Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J. Immunol. 189, 4405–4416 (2012).
Capasso, M. et al. HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species. Nat. Immunol. 11, 265–272 (2010).
Jellusova, J. et al. Gsk3 is a metabolic checkpoint regulator in B cells. Nat. Immunol. 18, 303–312 (2017).
Diaz-Munoz, M. D. et al. The RNA-binding protein HuR is essential for the B cell antibody response. Nat. Immunol. 16, 415–425 (2015).
Chen, M. et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat. Med. 20, 503–510 (2014).
Baumgarth, N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat. Rev. Immunol. 11, 34–46 (2011).
Pillai, S. & Cariappa, A. The follicular versus marginal zone B lymphocyte cell fate decision. Nat. Rev. Immunol. 9, 767–777 (2009).
Clarke, A. J., Riffelmacher, T., Braas, D., Cornall, R. J. & Simon, A. K. B1a B cells require autophagy for metabolic homeostasis and self-renewal. J. Exp. Med. 215, 399–413 (2018). This study demonstrates that B1 cells are bioenergetically more active than B2 cells, and that they acquire exogeneous fatty acids and store them in lipid droplets.
Hauck, A. K. & Bernlohr, D. A. Oxidative stress and lipotoxicity. J. Lipid Res. 57, 1976–1986 (2016).
Diskin, C. & Palsson-McDermott, E. M. Metabolic modulation in macrophage effector function. Front. Immunol. 9, 270 (2018).
Geeraerts, X., Bolli, E., Fendt, S. M. & Van Ginderachter, J. A. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front. Immunol. 8, 289 (2017).
Rodriguez-Prados, J. C. et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185, 605–614 (2010).
Freemerman, A. J. et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289, 7884–7896 (2014).
Michl, J., Ohlbaum, D. J. & Silverstein, S. C. 2-Deoxyglucose selectively inhibits Fc and complement receptor-mediated phagocytosis in mouse peritoneal macrophages II. Dissociation of the inhibitory effects of 2-deoxyglucose on phagocytosis and ATP generation. J. Exp. Med. 144, 1484–1493 (1976).
Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017).
Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008).
Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 21, 65–80 (2015).
Luo, W. et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744 (2011).
Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e13 (2016). This work demonstrates that M1 macrophages repurpose their mitochondria from ATP production to ROS generation in order to sustain IL-1β responses.
Melillo, G. et al. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J. Exp. Med. 182, 1683–1693 (1995).
Melillo, G., Taylor, L. S., Brooks, A., Cox, G. W. & Varesio, L. Regulation of inducible nitric oxide synthase expression in IFN-γ-treated murine macrophages cultured under hypoxic conditions. J. Immunol. 157, 2638–2644 (1996).
Everts, B. et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422–1431 (2012). This work shows that NO inhibits OXPHOS in inflammatory dendritic cells.
Galvan-Pena, S. et al. Malonylation of GAPDH is an inflammatory signal in macrophages. Nat. Commun. 10, 338 (2019).
Wolf, A. J. et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166, 624–636 (2016).
Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).
Haschemi, A. et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 15, 813–826 (2012).
Muri, J., Thut, H., Feng, Q. & Kopf, M. Thioredoxin-1 distinctly promotes NF-κB target DNA binding and NLRP3 inflammasome activation independently of Txnip. eLife 9, e53627 (2020). This work provides genetic evidence that TRX1 regulates NF-κB-mediated and NLRP3-mediated inflammatory responses in dendritic cells and macrophages.
Ghesquiere, B., Wong, B. W., Kuchnio, A. & Carmeliet, P. Metabolism of stromal and immune cells in health and disease. Nature 511, 167–176 (2014).
Cameron, A. M. et al. Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage. Nat. Immunol. 20, 420–432 (2019).
Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1–IKKε supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323–332 (2014).
Rodriguez, A. E. et al. Serine metabolism supports macrophage IL-1β production. Cell Metab. 29, 1003–1011.e4 (2019). This paper reveals the role of serine-dependent GSH biosynthesis in supporting IL-1β production.
Kang, R. et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe 24, 97–108.e4 (2018).
Kapralov, A. A. et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat. Chem. Biol. 16, 278–290 (2020).
Huang, S. C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846–855 (2014).
Vats, D. et al. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).
Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).
West, A. P. et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–480 (2011).
Billingham, L. K. & Chandel, N. S. NAD–biosynthetic pathways regulate innate immunity. Nat. Immunol. 20, 380–382 (2019).
Di Gioia, M. et al. Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation. Nat. Immunol. 21, 42–53 (2020).
Infantino, V. et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J. 438, 433–436 (2011).
Bailey, J. D. et al. Nitric oxide modulates metabolic remodeling in inflammatory macrophages through TCA cycle regulation and itaconate accumulation. Cell Rep. 28, 218–230.e7 (2019).
Michelucci, A. et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl Acad. Sci. USA 110, 7820–7825 (2013).
Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).
Qin, W. et al. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat. Chem. Biol. 15, 983–991 (2019).
Hooftman, A. et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab. 32, 468–478 (2020).
Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis. Nature 556, 501–504 (2018).
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018). This study shows that the metabolite itaconate activates NRF2 and induces an anti-inflammatory programme in M1 macrophages.
Muri, J., Wolleb, H., Broz, P., Carreira, E. M. & Kopf, M. Electrophilic Nrf2 activators and itaconate inhibit inflammation at low dose and promote IL-1β production and inflammatory apoptosis at high dose. Redox Biol. 36, 101647 (2020).
Thimmulappa, R. K. et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Invest. 116, 984–995 (2006).
Liu, M. et al. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int. 76, 277–285 (2009).
Khor, T. O. et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 66, 11580–11584 (2006).
Osburn, W. O. et al. Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. Int. J. Cancer 121, 1883–1891 (2007).
Lamle, J. et al. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134, 1159–1168 (2008).
Chen, P. C. et al. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: critical role for the astrocyte. Proc. Natl Acad. Sci. USA 106, 2933–2938 (2009).
Johnson, D. A., Amirahmadi, S., Ward, C., Fabry, Z. & Johnson, J. A. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol. Sci. 114, 237–246 (2010).
Cho, H. Y. & Kleeberger, S. R. Nrf2 protects against airway disorders. Toxicol. Appl. Pharmacol. 244, 43–56 (2010).
Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016). This work shows that NRF2 binds to the proximity of pro-inflammatory genes and thus inhibits RNA polymerase II recruitment in macrophages.
Muri, J. et al. Cyclopentenone prostaglandins and structurally related oxidized lipid species instigate and share distinct pro- and anti-inflammatory pathways. Cell Rep. 30, 4399–4417.e7 (2020). This study shows that whereas electrophilic lipid mediators inhibit transcription of pro-inflammatory cytokines at low concentrations, they induce inflammatory apoptosis and IL-1β processing at high doses.
Bretscher, P. et al. Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2. EMBO Mol. Med. 7, 593–607 (2015).
Chartoumpekis, D. V. et al. Nrf2 represses FGF21 during long-term high-fat diet-induced obesity in mice. Diabetes 60, 2465–2473 (2011).
Pi, J. et al. Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J. Biol. Chem. 285, 9292–9300 (2010).
Freigang, S. et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur. J. Immunol. 41, 2040–2051 (2011).
Okada, K. et al. Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J. Gastroenterol. 48, 620–632 (2013).
Ruotsalainen, A. K. et al. The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovasc. Res. 98, 107–115 (2013).
Zhao, C., Gillette, D. D., Li, X., Zhang, Z. & Wen, H. Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation. J. Biol. Chem. 289, 17020–17029 (2014).
Heiss, E. H., Schachner, D., Zimmermann, K. & Dirsch, V. M. Glucose availability is a decisive factor for Nrf2-mediated gene expression. Redox Biol. 1, 359–365 (2013).
Baardman, J. et al. A defective pentose phosphate pathway reduces inflammatory macrophage responses during hypercholesterolemia. Cell Rep. 25, 2044–2052.e5 (2018).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).
Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).
Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10, 210–215 (2010).
Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011). This paper shows that mitochondrial ROS can activate the NLRP3 inflammasome.
Zhong, Z. et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198–203 (2018).
Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012). This paper demonstrates that mitochondrial DNA released during cell death causes activation of the NLRP3 inflammasome.
van Bruggen, R. et al. Human NLRP3 inflammasome activation is Nox1–4 independent. Blood 115, 5398–5400 (2010).
Meissner, F. et al. Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease. Blood 116, 1570–1573 (2010).
Chauhan, D. et al. BAX/BAK-induced apoptosis results in caspase-8-dependent IL-1β maturation in macrophages. Cell Rep. 25, 2354–2368.e5 (2018).
Vince, J. E. et al. The mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1β activation. Cell Rep. 25, 2339–2353.e4 (2018).
Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).
Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012).
Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).
Meissner, F., Molawi, K. & Zychlinsky, A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat. Immunol. 9, 866–872 (2008).
Kim, Y. M., Talanian, R. V., Li, J. & Billiar, T. R. Nitric oxide prevents IL-1β and IFN-γ-inducing factor (IL-18) release from macrophages by inhibiting caspase-1 (IL-1β-converting enzyme). J. Immunol. 161, 4122–4128 (1998).
Mishra, B. B. et al. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat. Immunol. 14, 52–60 (2013).
Matthews, J. R., Wakasugi, N., Virelizier, J. L., Yodoi, J. & Hay, R. T. Thioredoxin regulates the DNA binding activity of NF-κB by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res. 20, 3821–3830 (1992).
Lee, K. N. et al. VDUP1 is required for the development of natural killer cells. Immunity 22, 195–208 (2005).
Cheng, F. et al. Impact of glutathione peroxidase-1 deficiency on macrophage foam cell formation and proliferation: implications for atherogenesis. PLoS ONE 8, e72063 (2013).
Blankenberg, S. et al. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N. Engl. J. Med. 349, 1605–1613 (2003).
Torzewski, M. et al. Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 27, 850–857 (2007).
Weinberg, E. O. et al. IL-33 induction and signaling are controlled by glutaredoxin-1 in mouse macrophages. PLoS ONE 14, e0210827 (2019).
Aesif, S. W. et al. Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced lung inflammation and alveolar macrophage activation. Am. J. Respir. Cell Mol. Biol. 44, 491–499 (2011).
Schulze-Topphoff, U. et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc. Natl Acad. Sci. USA 113, 4777–4782 (2016).
Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).
Humphries, F. et al. Succination inactivates gasdermin D and blocks pyroptosis. Science (2020).
Xiao, W., Wang, R. S., Handy, D. E. & Loscalzo, J. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid. Redox Signal. 28, 251–272 (2018).
Rhee, S. G. & Kil, I. S. Multiple functions and regulation of mammalian peroxiredoxins. Annu. Rev. Biochem. 86, 749–775 (2017).
Lu, S. C. Glutathione synthesis. Biochim. Biophys. Acta 1830, 3143–3153 (2013).
Suzuki, T., Motohashi, H. & Yamamoto, M. Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharmacol. Sci. 34, 340–346 (2013).
Arner, E. S. & Holmgren, A. The thioredoxin system in cancer. Semin. Cancer Biol. 16, 420–426 (2006).
Urig, S. & Becker, K. On the potential of thioredoxin reductase inhibitors for cancer therapy. Semin. Cancer Biol. 16, 452–465 (2006).
Mandal, P. K. et al. Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation. Cancer Res. 70, 9505–9514 (2010).
Kinowaki, Y. et al. Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma. Lab. Invest. 98, 609–619 (2018).
Dai, L. et al. Genomic analysis of xCT-mediated regulatory network: identification of novel targets against AIDS-associated lymphoma. Oncotarget 6, 12710–12722 (2015).
Trzeciecka, A. et al. Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma. Oncotarget 7, 1717–1731 (2016).
Weyand, C. M. & Goronzy, J. J. Immunometabolism in early and late stages of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 291–301 (2017).
Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).
Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8, 331ra338 (2016).
Weyand, C. M., Shen, Y. & Goronzy, J. J. Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic. Biol. Med. 125, 36–43 (2018).
Brudno, J. N. & Kochenderfer, J. N. Chimeric antigen receptor T-cell therapies for lymphoma. Nat. Rev. Clin. Oncol. 15, 31–46 (2018).
Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013).
Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab. 23, 63–76 (2016).
Pilipow, K. et al. Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity. JCI Insight 3(2018).
Scheffel, M. J. et al. Efficacy of adoptive T-cell therapy is improved by treatment with the antioxidant N-acetyl cysteine, which limits activation-induced T-cell death. Cancer Res. 76, 6006–6016 (2016).
Scheffel, M. J. et al. N-Acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner. Cancer Immunol. Immunother. 67, 691–702 (2018).
Apostolova, N. & Victor, V. M. Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications. Antioxid. Redox Signal. 22, 686–729 (2015).
Gioscia-Ryan, R. A. et al. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J. Physiol. 592, 2549–2561 (2014).
Chouchani, E. T. et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat. Med. 19, 753–759 (2013).
Wani, W. Y. et al. Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain. Neuropharmacology 61, 1193–1201 (2011).
Chacko, B. K. et al. Prevention of diabetic nephropathy in Ins2+/–AkitaJ mice by the mitochondria-targeted therapy MitoQ. Biochem. J. 432, 9–19 (2010).
Mercer, J. R. et al. The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/–/ApoE–/– mice. Free Radic. Biol. Med. 52, 841–849 (2012).
Dashdorj, A. et al. Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines. BMC Med. 11, 178 (2013).
Zang, Q. S. et al. Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model. Am. J. Physiol. Heart Circ. Physiol 302, H1847–H1859 (2012).
Sova, M. & Saso, L. Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review. Drug Des. Devel Ther. 12, 3181–3197 (2018).
Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).
Mitsuishi, Y., Motohashi, H. & Yamamoto, M. The Keap1–Nrf2 system in cancers: stress response and anabolic metabolism. Front. Oncol. 2, 200 (2012).
Rojo de la Vega, M., Chapman, E. & Zhang, D. D. NRF2 and the hallmarks of cancer. Cancer Cell 34, 21–43 (2018).
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).
The authors declare no competing interests.
Peer review information
Nature Reviews Immunology thanks Luke O’Neill, Navdeep Chandel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- 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.
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.
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).
About this article
Cite this article
Muri, J., Kopf, M. Redox regulation of immunometabolism. Nat Rev Immunol 21, 363–381 (2021). https://doi.org/10.1038/s41577-020-00478-8