‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease
Abstract
Iron homeostasis and macrophage biology are closely interconnected. On the one hand, iron exerts multiple effects on macrophage polarization and functionality. On the other hand, macrophages are central for mammalian iron homeostasis. The phagocytosis of senescent erythrocytes and their degradation by macrophages enable efficient recycling of iron and the maintenance of systemic iron balance. Macrophages express multiple molecules and proteins for the acquisition and utilization of iron and many of these pathways are affected by inflammatory signals. Of note, iron availability within macrophages has significant effects on immune effector functions and metabolic pathways within these cells. This review summarizes the physiological and pathophysiological aspects of macrophage iron metabolism and highlights its relevant consequences on immune function and in common diseases such as infection and atherosclerosis.
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These data support the general idea that modulation of macrophage iron homeostasis is a promising way to control their immune functions and alter myeloid-driven disease processes in infection, auto-immunity, atherosclerosis, and possibly cancer.
“These novel and exciting data support the general idea that the modulation of macrophage iron homeostasis is a promising way to control their immune functions and alter myeloid-driven disease processes in infection, auto-immunity, atherosclerosis, and possibly also cancer [143, 167]”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [167]
The functional form of Nramp1 in myeloid cells shifts the balance in T helper cell activity towards Th1, which may increase resistance to infections while increasing susceptibility to autoimmune diseases.
“In addition, the functional form of Nramp1 in myeloid cells shifts the balance in T helper cell activity towards Th1, which may increase resistance to infections while increasing the susceptibility to autoimmune diseases [167, 226].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [167]
Monocytes/macrophages deliver approximately 95% of the iron required for de novo heme/hemoglobin synthesis during erythropoiesis.
“Monocytes/macrophages (Mø) play a central role in the maintenance of Fe homeostasis, delivering approximately 95% of the Fe required to support de novo heme/hemoglobin synthesis during erythropoiesis [48,49] (Fig 1).”
From The Iron age of host–microbe interactions (2015) · cites this paper as [48]
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Michalska, M., Machtoub, L. H., Manthey, H. D., Bauer, E., Herold, V., Krohne, G., Lykowsky, G., Hildenbrand, M. F., Kampf, T., Jakob, P. M., et al. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.255224 · Cited by 78 · see citing works
Fargion, S., Fracanzani, A. L., Brando, B., Arosio, P., Levi, S., & Fiorelli, G. (1991) · Blood · doi:10.1182/blood.v78.4.1056.1056 · Cited by 78 · see citing works
Role of iron and ferritin in TNFα‐induced apoptosis in HeLa cells
Cozzi, A., Levi, S., Corsi, B., Santambrogio, P., Campanella, A., Gerardi, G., & Arosio, P. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00114-5 · Cited by 76 · see citing works
Leishmania-Mediated Inhibition of Iron Export Promotes Parasite Replication in Macrophages
Ben-Othman, R., Flannery, A. R., Miguel, D. C., Ward, D. M., Kaplan, J., & Andrews, N. W. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1003901 · Cited by 76 · see citing works
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Role of iron homeostasis in trypanosomiasis-associated anemia
Stijlemans, B., Vankrunkelsven, A., Brys, L., Magez, S., & BAETSELIER, P. D. (2008) · Immunobiology · doi:10.1016/j.imbio.2008.07.023 · Cited by 74 · see citing works
Chau, J. Y., Tiffany, C. M., Nimishakavi, S., Lawrence, J. A., Pakpour, N., Mooney, J. P., Lokken, K. L., Caughey, G. H., Tsolis, R. M., & Luckhart, S. (2013) · Infection and Immunity · doi:10.1128/iai.00380-13 · Cited by 74 · see citing works
Van Zandt, K. E., Sow, F. B., Florence, W. C., Zwilling, B. S., Satoskar, A. R., Schlesinger, L. S., & Lafuse, W. P. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.1107781 · Cited by 74 · see citing works
Theurl, I., Fritsche, G., Ludwiczek, S., Garimorth, K., Bellmann-Weiler, R., & Weiss, G. (2005) · BioMetals · doi:10.1007/s10534-005-3710-1 · Cited by 72 · see citing works
Self-citationFritsche, G., Nairz, M., Libby, S. J., Fang, F. C., & Weiss, G. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.1111554 · Cited by 72 · see citing works
Self-citationMoura, D. F., Mattos, K. A., Amadeu, T. P., Andrade, P. R., Sales, J. D. S., Schmitz, V., Nery, J. A. C., Pinheiro, R. O., & Sarno, E. N. (2012) · European Journal of Immunology · doi:10.1002/eji.201142198 · Cited by 71 · see citing works
Wermke, M., Schmidt, A., Middeke, J. M., Sockel, K., Bonin, M. V., Schönefeldt, C., Mair, S., Plodeck, V., Laniado, M., Weiß, G., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1683 · Cited by 71 · see citing works
Self-citationRegulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection
Liu, Z., Reba, S., Chen, W.-D., Porwal, S. K., Boom, W. H., Petersen, R. B., Rojas, R., Viswanathan, R., & Devireddy, L. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20132629 · Cited by 70 · see citing works
Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression
Theurl, M., Theurl, I., Hochegger, K., Obrist, P., Subramaniam, N., van Rooijen, N., Schuemann, K., & Weiss, G. (2008) · Journal of Molecular Medicine · doi:10.1007/s00109-008-0346-y · Cited by 69 · see citing works
Self-citationLi, W., Xu, L.-H., Forssell, C., Sullivan, J. L., & Yuan, X.-M. (2008) · Experimental Biology and Medicine · doi:10.3181/0711-rm-320 · Cited by 69 · see citing works
Jan, T., Shen, Liang, Wang, C., & Liao (2012) · International Journal of Nanomedicine · doi:10.2147/ijn.s31054 · Cited by 68 · see citing works
Halaas, Ø., Steigedal, M., Haug, M., Awuh, J. A., Ryan, L., Brech, A., Sato, S., Husebye, H., Cangelosi, G. A., Akira, S., et al. (2010) · The Journal of Infectious Diseases · doi:10.1086/650493 · Cited by 68 · see citing works
Transferrin iron starvation therapy for lethal bacterial and fungal infections
Lin, L., Pantapalangkoor, P., Tan, B., Bruhn, K. W., Ho, T., Nielsen, T., Skaar, E. P., Zhang, Y., Bai, R., Wang, A., et al. (2014) · Journal of Infectious Diseases · doi:10.1093/infdis/jiu049 · Cited by 68 · see citing works
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Targeting iron metabolism in drug discovery and delivery
Crielaard, B. J., Lammers, T., & Rivella, S. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.248 · Cited by 352 · see citing works
Vinchi, F., Costa da Silva, M., Ingoglia, G., Petrillo, S., Brinkman, N., Zuercher, A., Cerwenka, A., Tolosano, E., & Muckenthaler, M. U. (2016) · Blood · doi:10.1182/blood-2015-08-663245 · Cited by 269 · see citing works
Oxidative Stress and the Homeodynamics of Iron Metabolism
Bresgen, N., & Eckl, P. (2015) · Biomolecules · doi:10.3390/biom5020808 · Cited by 247 · see citing works
The Iron age of host–microbe interactions
Soares, M. P., & Weiss, G. (2015) · The EMBO Reports · doi:10.15252/embr.201540558 · Cited by 227 · see citing works
Self-citation“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1944-8 · Cited by 178 · see citing works
Self-citationIron and innate antimicrobial immunity-depriving the pathogen, defending the host
Nairz, M., Dichtl, S., Schroll, A., Haschka, D., Tymoszuk, P., Theurl, I., & Weiss, G. (2018) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2018.03.007 · Cited by 123 · see citing works
Self-citationAnemia of chronic disorders: new diagnostic tools and new treatment strategies
Weiss, G. (2015) · Seminars in Hematology · doi:10.1053/j.seminhematol.2015.07.004 · Cited by 116 · see citing works
Vlasveld, L. T., Janssen, R., Bardou-Jacquet, E., Venselaar, H., Hamdi-Roze, H., Drakesmith, H., & Swinkels, D. W. (2019) · Pharmaceuticals · doi:10.3390/ph12030132 · Cited by 57 · see citing works
Leftin, A., Zhao, H., Turkekul, M., de Stanchina, E., Manova, K., & Koutcher, J. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-11899-2 · Cited by 33 · see citing works
Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes
Haschka, D., Petzer, V., Kocher, F., Tschurtschenthaler, C., Schaefer, B., Seifert, M., Sopper, S., Sonnweber, T., Feistritzer, C., Arvedson, T. L., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.98867 · Cited by 34 · see citing works
Self-citationComparison of iron-reduced and iron-supplemented semisynthetic diets in T cell transfer colitis
Markota, A., Metzger, R., Heiseke, A. F., Jandl, L., Dursun, E., Eisenächer, K., Reindl, W., Haller, D., & Krug, A. B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0218332 · Cited by 9 · see citing works
- Authors
- Nairz, M., Schroll, A., Demetz, E., Tancevski, I., Theurl, I., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- Corresponding author
- Nairz, Manfred
- Weiss, Günter
- Venue
- Immunobiology
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 220
- Issue
- 2
- Pages
- 280-294
- ISSN
- 0171-2985 (ISSN-L)
- OpenAlex
- W2009433296
- Cited by
- 89
- References
- 244
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 2 · 2023: 2 · 2022: 14 · 2021: 8 · 2020: 4 · 2019: 10 · 2018: 9 · 2017: 10 · 2016: 7 · 2015: 11 · 2014: 2
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Immunobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Austrian Research Funds
- EU-7th framework (EUROCALIN)
- Medical University of Innsbruck
- Verein zur Förderung von Forschung und Weiterbildung in Infektiologie und Immunologie an der Medizinischen Universität Innsbruck
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- iron homeostasis, macrophage polarization, erythrophagocytosis, heme degradation, iron recycling, inflammation, macrophage metabolism, infection, atherosclerosis
- MeSH terms
- Anemia, Hemolytic, Animals, Homeostasis, Humans, Immunity, Inflammation, Iron, Macrophages, Neoplasms, Mononuclear Phagocyte System, Iron Overload, Immunomodulation
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.
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