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Macrophages and Systemic Iron Homeostasis
Open accessAbstract
As a principal aspect of their scavenging function, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recover iron, mainly for the production of hemoglobin in new erythrocytes but also for other carriers and enzymes requiring iron. Splenic red pulp macrophages are specialized for iron recycling with increased expression of proteins for the uptake of hemoglobin, breakdown of heme and the export of iron. In humans, recycling macrophages contribute the majority of the iron flux into extracellular fluid, exceeding the contribution of dietary iron absorption and release of stored iron from hepatocytes. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. In addition to their homeostatic role, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. This review discusses the iron-scavenging function of macrophages in the context of iron homeostasis and host defense.
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“Inside infected macrophages, a pathogen's access to Fe may be limited by natural resistance-associated macrophage protein 1 (SLC11A1, formerly Nramp1).”
From Strategies of intracellular pathogens for obtaining iron from the environment (2015) · cites this paper as [20]
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“Therefore, the bulk of iron needed for homeostasis (mainly for red blood cell (RBC) production) is provided by the MYPS, more specifically the myeloid cells, that recycles senescent RBCs at the level of the liver, spleen, and bone marrow via erythrophagocytosis and allows their iron reutilization [95] (see Figure 2).”
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Yuan, W., Zhang, X., & Fan, X. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45070369 · Cited by 29
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“Kupffer cells, the resident macrophages in the liver, are involved in many immune and homeostatic functions such as clearing gut-derived toxins and pathogens from the blood, removal of damaged erythrocytes, as well as iron, bilirubin, and cholesterol metabolism (Ganz, 2012; T’Jonck et al., 2018).”
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Lupica-Tondo, G. L., Arner, E. N., Mogilenko, D. A., & Voss, K. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1441338 · Cited by 30
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“Macrophages are critical to host defense and play a key role in regulating systemic iron homeostasis in health and diseases [3].”
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“One strategy of the immune system for inhibiting bacterial cell proliferation is the sequestration of iron from the circulation by macrophages, which inhibits bacterial cell proliferation [24,25].”
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“Atheroprotective Potential of LXRα in Iron-Enriched M2 Polarized Macrophages Traditionally, sequestration of iron by inflammatory M1 macrophages has been reported as a mechanism of defense against bacterial proliferation.(21) In addition, M1 macrophages have been shown to sequester iron in the context of chronic infla…”
BackgroundJi, F., Lee, H., Rheem, H., Liu, J., & Kim, J.-H. (2025) · Scientific Reports · doi:10.1038/s41598-025-09519-5 · Cited by 15
“Prussian blue staining revealed significant accumulation of iron in the skeletal muscle of obese mice, consistent with reports of dysregulated iron metabolism in obesity 36 .”
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Iron Fortification and Supplementation: Fighting Anemia of Chronic Diseases or Fueling Obesity?
El-Mallah, C. A., Beyh, Y. S., & Obeid, O. (2021) · Current Developments in Nutrition · doi:10.1093/cdn/nzab032 · Cited by 12
“Therefore, these proteins can act as a double-edged sword where their constantly elevated concentrations in the blood, due to reasons other than high iron availability, can lead to defective duodenal iron absorption (31, 61) and increased macrophage recycling (31, 62).”
BackgroundTasinov, O., Kiselova-Kaneva, Y. D., Ivanova, D. P., Pasheva, M. G., Vankova, D. G., & Ivanova, D. G. (2021) · Homeopathy · doi:10.1055/s-0041-1731312 · Cited by 12
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“32 Moreover, during inflammation, the concentration of transferrin drops in connection with the disturbed metabolism of this protein.”
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Serum Ferritin Levels: A Clinical Guide in Patients With Hair Loss
Zhang, D. (2023) · Cutis · doi:10.12788/cutis.0837 · Cited by 10
Disorders of Iron Metabolism: Iron Deficiency and Iron Overload and Anemia of Chronic Diseases
Rivella, S., & Crielaard, B. J. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-386456-7.07903-x · Cited by 9
Macrophages: Past, Present and Future
Herwald, H., & Egesten, A. (2013) · Journal of Innate Immunity · doi:10.1159/000356293 · Cited by 9
Macrophages and Iron Metabolism
Ganz, T. (2017) · ASM Press eBooks · doi:10.1128/9781555819194.ch46 · Cited by 10
Self-citationInnate Immune Functions of Macrophages in Different Tissue Environments
Gordon, S. (2012) · Journal of Innate Immunity · doi:10.1159/000339280 · Cited by 9
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In VitroStudies on the Immunomodulatory Effects ofPulicaria crispaExtract on Human THP-1 Monocytes
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“Such functions include regulation of bone remodeling [3], erythropoiesis [4], brain development [5], iron recycling [6], and tissue regeneration [7].”
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Smart Cell Therapy: an industry perspective on macrophages as living drugs
Rodgers, D. T., Novobrantseva, T. I., & Bárcia, R. N. (2024) · Cytotherapy · doi:10.1016/j.jcyt.2024.12.002 · Cited by 7
Administration of α-Klotho Does Not Rescue Renal Anemia in Mice
Park, M. Y., Hénaff, C. L., & Sitara, D. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2022.924915 · Cited by 8
“Hepcidin, a liver-secreted protein, is a master regulator of iron metabolism controlling the release of iron from the stores into the circulation (47, 48).”
BackgroundRadakovich, L. B., & Olver, C. S. (2016) · Veterinary Clinics of North America Small Animal Practice · doi:10.1016/j.cvsm.2016.07.002 · Cited by 9
Does iron overload in metabolic syndrome affect macrophage profile? A case control study
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“However, when these molecules are exposed to the extracellular environment, they acquire secondary functions, such as mediating inflammation (Ganz, 2012; Meegan et al ., 2020; Qin et al ., 2022; Sharma et al ., 2022), cytotoxicity (Hsia and Everse, 1996; Jeney et al ., 2002; Wang et al ., 2002;…”
Wang, C., Melgar-Bermudez, E., Welch, D., Dagbay, K. B., Bhattacharya, S., Lema, E., Daman, T. H., Sierra, O., Todorova, R., Drame, P. M., et al. (2025) · American Journal of Hematology · doi:10.1002/ajh.27578 · Cited by 7
“As the biggest consumer of circulating iron, human bone marrow requires 20–25 mg of iron each day for hemoglobin synthesis, but only 1–2 mg comes from the diet [75, 76].”
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Králová, B., Sochorcova, L., Song, J., Jahoda, O., Kapralova, K., Prchal, J. T., Divoký, V., & Horváthová, M. (2022) · American Journal of Hematology · doi:10.1002/ajh.26658 · Cited by 7
“The recycling of iron through erythrophagocytosis by macrophages is a major contributor to systemic iron homeostasis.(43) We previously showed that the dramatic decrease of Hct in mtHEPOR homozygotes”
BackgroundEvaluation of Hepcidin Level in COVID-19 Patients Admitted to the Intensive Care Unit
Ciotti, M., Nuccetelli, M., Pieri, M., Petrangeli, C. M., Giovannelli, A., Cosio, T., Rosa, L., Valenti, P., Leonardis, F., Legramante, J. M., et al. (2022) · Diagnostics · doi:10.3390/diagnostics12112665 · Cited by 6
“Hepcidin sequesters iron mainly through macrophages [10].”
Dervas, E., Michalopoulou, E., Hepojoki, J., Thiele, T., Baggio, F., Hetzel, U., & Kipar, A. (2024) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2024.105302 · Cited by 6
“Red pulp macrophages, thought to function as a filter by facilitating clearance of senescent red blood cells and regulating iron metabolism, are most abundant and are found in the perifollicular zone (Ganz, 2012; Kurotaki et al., 2015; Mebius and Kraal, 2005).”
Hepcidin independent iron recycling in a mouse model of β‐thalassaemia intermedia
Frazer, D. M., Wilkins, S. J., Mirciov, C. S. G., Dunn, L. A., & Anderson, G. J. (2016) · British Journal of Haematology · doi:10.1111/bjh.14206 · Cited by 6
“Macrophages are responsible for removing old or damaged red blood cells from the circulation, extracting the iron from haemoglobin and releasing it back into the plasma (Ganz, 2012).”
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Impact of iron status on kidney outcomes in kidney transplant recipients
Kim, H. J., Ro, H., Kang, K. P., Ryu, J.-H., Kim, M.-G., Huh, K. H., Park, J. B., Kim, C., Han, S., Kim, H. W., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-28125-x · Cited by 6
Metadata
- Authors
- Ganz, T.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Ganz, Tomas
- ORCID
- Ganz, Tomas
- Venue
- Journal of Innate Immunity
- Publisher
- S. Karger AG
- Published
- 2012
- Volume
- 4
- Issue
- 5-6
- Pages
- 446-453
- ISSN
- 1662-811X (ISSN-L)
- 1662-8128
- PMC
- PMC6741611
- OpenAlex
- W2041361488
- Cited by
- 281
- References
- 47
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 18 · 2023: 13 · 2022: 27 · 2021: 21 · 2020: 21 · 2019: 17 · 2018: 20 · 2017: 33 · 2016: 18 · 2015: 26 · 2014: 20 · 2013: 15 · 2012: 3
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Innate Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Physical Sciences › Materials Science › Metals and Alloys › Iron and Steelmaking Processes
- Keywords
- macrophages, hepatic macrophages, hepcidin, ferroportin, iron export, heme degradation, host defense
- MeSH terms
- Ferroportin, Adult, Animals, Erythrocytes, Homeostasis, Humans, Iron, Macrophages, Male, Antimicrobial Cationic Peptides, Cation Transport Proteins, Mice, Cytophagocytosis, Hepcidins
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