A broken Krebs cycle in macrophages
Open accessAbstract
Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.
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The first TCA cycle break occurs at isocitrate dehydrogenase, leading to accumulation of citrate, the precursor for itaconate.
“The first break occurs at isocitrate dehydrogenase, leading to the accumulation of citrate, the precursor for itaconate”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [24]
The second TCA cycle break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.
“the second break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [24]
Cites
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335 · see citing works
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176 · see citing works
Jha, A. K., Huang, S. C.-C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., Loginicheva, E., Chmielewski, K., Stewart, K. M., Ashall, J., Everts, B., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.005 · Cited by 2,066 · see citing works
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, A., Cordes, T., Ghelfi, J., Pailot, A., Reiling, N., Goldmann, O., Binz, T., Wegner, A., Tallam, A., Rausell, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218599110 · Cited by 1,191 · see citing works
Metabolism of Inflammation Limited by AMPK and Pseudo-Starvation
O'Neill, L. A. J., & Hardie, D. G. (2013) · Nature · doi:10.1038/nature11862 · Cited by 1,133 · see citing works
Self-citationMetabolic regulation of immune responses
Ganeshan, K., & Chawla, A. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120236 · Cited by 926 · see citing works
The mitochondrial citrate carrier: a new player in inflammation
Infantino, V., Convertini, P., Cucci, L., Panaro, M. A., Noia, M. A. D., Calvello, R., Palmieri, F., & Iacobazzi, V. (2011) · Biochemical Journal · doi:10.1042/bj20111275 · Cited by 386 · see citing works
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Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation
Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., & Newsholme, P. (2018) · Nutrients · doi:10.3390/nu10111564 · Cited by 1,261 · see citing works
Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.685792 · Cited by 526 · see citing works
Krebs cycle Reborn in macrophage immunometabolism
Ryan, D. G., & O'Neill, L. A. J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-081619-104850 · Cited by 444 · see citing works
Self-citationMitochondria in innate immune signaling
Banoth, B., & Cassel, S. L. (2018) · Translational Research · doi:10.1016/j.trsl.2018.07.014 · Cited by 410 · see citing works
Metabolic regulation of inflammation
Gaber, T., Strehl, C., & Buttgereit, F. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.37 · Cited by 320 · see citing works
Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight
Palmieri, E. M., McGinity, C., Wink, D. A., & McVicar, D. W. (2020) · Metabolites · doi:10.3390/metabo10110429 · Cited by 237 · see citing works
“These findings led to the suggestion that in polarized macrophages, pseudo-hypoxia, caused by reduction in α-KG /succinate ratios and suppression of dioxygenase activity [113,114], leads to HIF1α stabilization and expression of Pyruvate Dehydrogenase Kinase 1 (Pdk1) that phosphorylates Pyruvate Dehydrogenase (PDH), re…”
BackgroundInfluentialGlutamine: Metabolism and Immune Function, Supplementation and Clinical Translation
Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., & Newsholme, P. (2018) · doi:10.20944/preprints201809.0459.v1 · Cited by 1,261 · see citing works
ten Brink, T., Damanik, F., Rotmans, J. I., & Moroni, L. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202301939 · Cited by 71 · see citing works
- Authors
- O’Neill, L. A. J.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 42
- Issue
- 3
- Pages
- 393-394
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2024275882
- Cited by
- 232
- References
- 7
- Citations by year
- 2026: 21 · 2025: 16 · 2024: 22 · 2023: 25 · 2022: 29 · 2021: 28 · 2020: 30 · 2019: 17 · 2018: 19 · 2017: 16 · 2016: 7 · 2015: 2
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- macrophage polarization, cellular metabolism, TCA cycle, metabolic reprogramming, metabolomics, metabolic pathways, macrophage metabolism
- MeSH terms
- Animals, Immunity, Innate, Macrophages, Mitochondria, Transcription, Genetic, Gene Regulatory Networks
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