Metabolism Supports Macrophage Activation
Open accessAbstract
Macrophages are found in most tissues of the body, where they have tissue- and context-dependent roles in maintaining homeostasis as well as coordinating adaptive responses to various stresses. Their capacity for specialized functions is controlled by polarizing signals, which activate macrophages by upregulating transcriptional programs that encode distinct effector functions. An important conceptual advance in the field of macrophage biology, emerging from recent studies, is that macrophage activation is critically supported by metabolic shifts. Metabolic shifts fuel multiple aspects of macrophage activation, and preventing these shifts impairs appropriate activation. These findings raise the exciting possibility that macrophage functions in various contexts could be regulated by manipulating their metabolism. Here, we review the rapidly evolving field of macrophage metabolism, discussing how polarizing signals trigger metabolic shifts and how these shifts enable appropriate activation and sustain effector activities. We also discuss recent studies indicating that the mitochondria are central hubs in inflammatory macrophage activation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
M1 macrophage oxygen consumption falls irrespective of NAD levels.
“the OCR of M1 macrophages declined, as expected19, regardless of NAD levels.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [19]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Macrophage activation and polarization: nomenclature and experimental guidelines
Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W., Goerdt, S., Gordon, S., Hamilton, J. A., Ivashkiv, L. B., Lawrence, T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.008 · Cited by 6,337 · see citing works
Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · 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
Mills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.064 · Cited by 2,291 · see citing works
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity
Cheng, S.-C., Quintin, J., Cramer, R. A., Shepardson, K. M., Saeed, S., Kumar, V., Giamarellos-Bourboulis, E. J., Martens, J. H. A., Rao, N. A., Aghajanirefah, A., et al. (2014) · Science · doi:10.1126/science.1250684 · Cited by 2,224 · see citing works
Davies, L. C., Jenkins, S. J., Allen, J. E., & Taylor, P. R. (2013) · Nature Immunology · doi:10.1038/ni.2705 · Cited by 2,096 · 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
HIF-1α is essential for myeloid cell-mediated inflammation
Cramer, T., Yamanishi, Y., Clausen, B. E., Förster, I., Pawlinski, R., Mackman, N., Haase, V. H., Jaenisch, R., Corr, M., Nizet, V., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00154-5 · Cited by 2,046 · see citing works
Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., & Schumacker, P. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001914200 · Cited by 2,000 · see citing works
Immunometabolism governs dendritic cell and macrophage function
O'Neill, L. A. J., & Pearce, E. J. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151570 · Cited by 1,715 · see citing works
Tlr signalling augments macrophage bactericidal activity through mitochondrial ros
West, A. P., Brodsky, I. E., Rahner, C., Woo, D. K., Erdjument-Bromage, H., Tempst, P., Walsh, M. C., Choi, Y., Shadel, G. S., & Ghosh, S. (2011) · Nature · doi:10.1038/nature09973 · Cited by 1,659 · see citing works
Lampropoulou, V., Sergushichev, A., Bambousková, M., Nair, S., Vincent, E. E., Loginicheva, E., Cervantes‐Barragán, L., Ma, X., Huang, S. C., Griss, T., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.004 · Cited by 1,547 · see citing works
Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming
Buck, M. D., O’Sullivan, D., Geltink, R. I. K., Curtis, J. D., Chang, C., Sanin, D. E., Qiu, J., Kretz, O., Braas, D., van der Windt, G. J. W., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.035 · Cited by 1,444 · see citing works
Palsson-McDermott, E. M., Curtis, A. M., Goel, G., Lauterbach, M. A. R., Sheedy, F. J., Gleeson, L. E., van den Bosch, M. W. M., Quinn, S. R., Domingo-Fernandez, R., Johnston, D. G. W., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.005 · Cited by 1,397 · see citing works
Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
Vats, D., Mukundan, L., Odegaard, J. I., Zhang, L., Smith, K. L., Morel, C. R., Greaves, D. R., Murray, P. J., & Chawla, A. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.011 · Cited by 1,369 · cited 3× · see citing works
“In M(IL-4) macrophages, their induction by STAT6 allows for upregulation of oxidative metabolism that is apparently needed for optimal activation (14, 15).”
BackgroundToll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis, R. J., Cross, J. R., Jung, E., Thompson, C. B., Jones, R. G., et al. (2010) · Blood · doi:10.1182/blood-2009-10-249540 · Cited by 1,246 · see citing works
Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages
Huang, S. C., Everts, B., Ivanova, Y., O’Sullivan, D., Nascimento, M., Smith, A. M., Beatty, W. L., Love-Gregory, L. D., Lam, W. Y., O’Neill, C. M., et al. (2014) · Nature Immunology · doi:10.1038/ni.2956 · Cited by 1,215 · 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
Everts, B., Amiel, E., Huang, S. C.-C., Smith, A. M., Chang, C.-H., Lam, W. Y., Redmann, V., Freitas, T. C., Blagih, J., van der Windt, G. J. W., et al. (2014) · Nature Immunology · doi:10.1038/ni.2833 · Cited by 1,064 · see citing works
Rodríguez-Prados, J.-C., Través, P. G., Cuenca, J., Rico, D., Aragonés, J., Martín-Sanz, P., Cascante, M., & Boscá, L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901698 · Cited by 1,022 · see citing works
Sağ, D., Carling, D., Stout, R. D., & Suttles, J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.12.8633 · Cited by 798 · see citing works
Lanaspa, M. A., Ishimoto, T., Li, N., Cicerchi, C., Orlicky, D. J., Ruzycki, P. A., Rivard, C. J., Inaba, S., Roncal-Jiménez, C. A., Bales, E. S., et al. (2013) · Nature Communications · doi:10.1038/ncomms3929 · Cited by 796 · see citing works
Kang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B., & Lee, C.-H. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.002 · Cited by 699 · see citing works
The Sedoheptulose Kinase CARKL Directs Macrophage Polarization through Control of Glucose Metabolism
Haschemi, A., Kosma, P., Gille, L., Evans, C. R., Burant, C. F., Starkl, P., Knapp, B., Haas, R., Schmid, J. A., Jandl, C., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.023 · Cited by 635 · see citing works
The TSC-mTOR pathway regulates macrophage polarization
Byles, V., Covarrubias, A. J., Ben‐Sahra, I., Lamming, D. W., Sabatini, D. M., Manning, B. D., & Horng, T. (2013) · Nature Communications · doi:10.1038/ncomms3834 · Cited by 628 · see citing works
Self-citationDrapier, J., & Hibbs, J. B. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.140.8.2829 · Cited by 592 · see citing works
mTORC2-IRF4 mediated metabolic reprograming is essential for macrophage alternative activation
Huang, S., Smith, A., Everts, B., Colonna, M., Pearce, E. L., Schilling, J., & Pearce, E. J. (2016) · Immunity · doi:10.1016/j.immuni.2016.09.016 · Cited by 579 · see citing works
Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells
Everts, B., Amiel, E., van der Windt, G. J. W., Freitas, T. C., Chott, R., Yarasheski, K. E., Pearce, E. L., & Pearce, E. J. (2012) · Blood · doi:10.1182/blood-2012-03-419747 · Cited by 532 · 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
Triggering the succinate receptor GPR91 on dendritic cells enhances immunity
Rubic, T., Lametschwandtner, G., Jost, S., Hinteregger, S., Kund, J., Carballido-Perrig, N., Schwärzler, C., Junt, T., Voshol, H., Meingassner, J. G., et al. (2008) · Nature Immunology · doi:10.1038/ni.1657 · Cited by 525 · see citing works
Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation
Covarrubias, A. J., Aksoylar, H., Yu, J., Snyder, N. W., Worth, A. J., Iyer, S. S., Wang, J., Ben‐Sahra, I., Byles, V., Polynne-Stapornkul, T., et al. (2016) · eLife · doi:10.7554/elife.11612 · Cited by 455 · see citing works
Self-citationLimiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling
York, A. G., Williams, K. J., Argus, J. P., Zhou, Q., Brar, G., Vergnes, L., Gray, E. E., Zhen, A., Wu, N. C., Yamada, D. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.045 · Cited by 446 · see citing works
Control of macrophage metabolism and activation by mTOR and Akt signaling
Covarrubias, A. J., Aksoylar, H., & Horng, T. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.08.001 · Cited by 419 · see citing works
Self-citationMitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense
Garaude, J., Acín-Pérez, R., Martínez-Cano, S., Enamorado, M., Ugolini, M., Nistal-Villán, E., Hervás-Stubbs, S., Pelegrín, P., Sander, L. E., Enríquez, J. A., et al. (2016) · Nature Immunology · doi:10.1038/ni.3509 · Cited by 313 · see citing works
Amino acid auxotrophy as a system of immunological control nodes
Murray, P. J. (2016) · Nature Immunology · doi:10.1038/ni.3323 · Cited by 248 · see citing works
Liu, L., Lu, Y., Martinez, J., Bi, Y., Lian, G., Wang, T., Milasta, S., Wang, J., Yang, M., Liu, G., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518000113 · Cited by 239 · see citing works
Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1
Fukuzumi, M., Shinomiya, H., Shimizu, Y., Ohishi, K., & Utsumi, S. (1996) · Infection and Immunity · doi:10.1128/iai.64.1.108-112.1996 · Cited by 224 · see citing works
Qualls, J. E., Subramanian, C., Rafi, W., Smith, A. M., Balouzian, L., DeFreitas, A. A., Shirey, K. A., Reutterer, B., Kernbauer, E., Stockinger, S., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.07.012 · Cited by 184 · see citing works
C13orf31 (FAMIN) is a central regulator of immunometabolic function
Cader, M. Z., Boroviak, K., Zhang, Q., Assadi, G., Kempster, S. L., Sewell, G. W., Saveljeva, S., Ashcroft, J., Clare, S., Mukhopadhyay, S., et al. (2016) · Nature Immunology · doi:10.1038/ni.3532 · Cited by 168 · see citing works
Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals
Kimura, T., Nada, S., Takegahara, N., Okuno, T., Nojima, S., Kang, S., Ito, D., Morimoto, K., Hosokawa, T., Hayama, Y., et al. (2016) · Nature Communications · doi:10.1038/ncomms13130 · Cited by 165 · see citing works
Amiel, E., Everts, B., Fritz, D. I., Beauchamp, S., Ge, B., Pearce, E. L., & Pearce, E. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302498 · Cited by 116 · see citing works
Matsumura, S., Kojidani, T., Kamioka, Y., Uchida, S., Haraguchi, T., Kimura, A., & Toyoshima, F. (2016) · Nature Communications · doi:10.1038/ncomms11858 · Cited by 100 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Metabolic Interactions in the Tumor Microenvironment
Lyssiotis, C. A., & Kimmelman, A. C. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.06.003 · Cited by 853 · see citing works
Reactive oxygen species (ROS) in macrophage activation and function in diabetes
Rendra, E., Riabov, V., Mossel, D. M., Sevastyanova, T., Harmsen, M. C., & Kzhyshkowska, J. (2019) · Immunobiology · doi:10.1016/j.imbio.2018.11.010 · Cited by 636 · see citing works
Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages
Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., Schmidt, M. S., Heckenbach, I., Kwok, R., Wiley, C. D., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00305-3 · Cited by 420 · see citing works
Lipid and Lipoprotein Metabolism in Microglia
Loving, B. A., & Bruce, K. D. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00393 · Cited by 255 · see citing works
Glutamine: 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
Monocytes present age-related changes in phospholipid concentration and decreased energy metabolism
Saare, M., Tserel, L., Haljasmägi, L., Taalberg, E., Peet, N., Eimre, M., Vetik, R., Kingo, K., Saks, K., Tamm, R., et al. (2020) · Aging Cell · doi:10.1111/acel.13127 · Cited by 79 · see citing works
Wang, A., Pope, S. D., Weinstein, J. S., Yu, S., Zhang, C., Booth, C. J., & Medzhitov, R. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820704116 · Cited by 67 · see citing works
- Authors
- Langston, P. K., Shibata, M., & Horng, T.
- Affiliations
- Harvard University (US)
- Corresponding author
- Horng, Tiffany
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2017-01-31
- Volume
- 8
- Pages
- 61-61
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC5281575
- OpenAlex
- W2582090837
- Cited by
- 185
- References
- 42
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 22 · 2023: 13 · 2022: 24 · 2021: 23 · 2020: 30 · 2019: 25 · 2018: 18 · 2017: 7
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01AI102964, R21AI119763)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- macrophage metabolism, macrophage activation, metabolic reprogramming, macrophage polarization, mitochondrial function, inflammatory macrophages, effector function, homeostasis, metabolic regulation of immunity
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
