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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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BackgroundTime-course assessment of the aggregation and metabolization of magnetic nanoparticles
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“Macrophages play a major role in iron homeostasis by recycling iron from senescent and dying red blood cells (RBC) back into the circulation and different tissues in the body (Andrews, 1999; Ganz, 2012; Hubler et al., 2015).”
BackgroundThe Repair of Skeletal Muscle Requires Iron Recycling through Macrophage Ferroportin
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The Heme Connection: Linking Erythrocytes and Macrophage Biology
Alam, M. Z., Devalaraja, S., & Haldar, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00033 · Cited by 72
“org January 2017 | Volume 8 | Article 33 iron exporter ferroportin (26, 31).”
BackgroundIron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores
Roth‐Walter, F. (2022) · Frontiers in Allergy · doi:10.3389/falgy.2022.859922 · Cited by 63
“Iron in the Circulation Iron is then delivered to most tissues via circulating transferrin, which carries roughly 2mg of this metal in the steady state (88).”
BackgroundMetabolic–Epigenetic Crosstalk in Macrophage Activation
Baardman, J., Licht, I., de Winther, M. P. J., & den Bossche, J. V. (2015) · Epigenomics · doi:10.2217/epi.15.71 · Cited by 64
Sex-specific effects of developmental lead exposure on the immune-neuroendocrine network
Kasten‐Jolly, J., & Lawrence, D. A. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.09.009 · Cited by 62
The Multiple Facets of Iron Recycling
Slusarczyk, P., & Mleczko‐Sanecka, K. (2021) · Genes · doi:10.3390/genes12091364 · Cited by 64
“First, constant exposure of RBCs to oxidative stress leads to the oxidation and denaturation of hemoglobin, as well to the formation of lipid peroxides, which both may promote the clustering of Band 3 protein [12,18].”
BackgroundLinking iron-deficiency with allergy: role of molecular allergens and the microbiome
Roth‐Walter, F., Pacios, L. F., Bianchini, R., & Jensen‐Jarolim, E. (2017) · Metallomics · doi:10.1039/c7mt00241f · Cited by 61
Catapano, A., Cimmino, F., Petrella, L., Pizzella, A., D’Angelo, M., Ambrosio, K., Marino, F., Sabbatini, A., Petrelli, M. D., Paolini, B., et al. (2025) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2025.109888 · Cited by 70
Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling
Adam, F. I., Bounds, P. L., Kissner, R., & Koppenol, W. H. (2015) · Chemical Research in Toxicology · doi:10.1021/tx500377b · Cited by 59
Hemolysis and immune regulation
Zhong, H., & Yazdanbakhsh, K. (2018) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000423 · Cited by 59
Diversity and environmental adaptation of phagocytic cell metabolism
Davies, L. C., Rice, C. M., McVicar, D. W., & Weiss, J. M. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.4ri0518-195r · Cited by 56
Olonisakin, T. F., Suber, T. L., Gonzalez-Ferrer, S., Xiong, Z., Peñaloza, H. F., van der Geest, R., Xiong, Y., Osei-Hwedieh, D. O., Tejero, J., Rosengart, M. R., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137468 · Cited by 54
“1 Introduction Approximately 2 × 1011 RBCs are synthesized each day in the healthy adult human (1, 2).”
BackgroundYang, B., Zhang, Y., Sun, L., Wang, J., Zhao, Z., Huang, Z., Mao, W., Xue, R., Chen, R., Luo, J., et al. (2022) · Advanced Functional Materials · doi:10.1002/adfm.202211251 · Cited by 56
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The intricate role of selenium and selenoproteins in erythropoiesis
Liao, C., Carlson, B. A., Paulson, R. F., & Prabhu, K. S. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.04.578 · Cited by 55
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The Ontogeny and Microenvironmental Regulation of Tumor-Associated Macrophages
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“Splenic macrophages and Kupffer cells maintain iron homeostasis by phagocytosing erythrocytes and recycling iron from hemoglobin (19, 49, 79).”
Liao, C., Hardison, R. C., Kennett, M. J., Carlson, B. A., Paulson, R. F., & Prabhu, K. S. (2018) · Blood · doi:10.1182/blood-2017-08-800607 · Cited by 54
Ferroptosis increases obesity: Crosstalk between adipocytes and the neuroimmune system
Zhang, S., Sun, Z., Jiang, X. Y., Lu, Z., Ding, L., Li, C., Tian, X., & Wang, Q. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1049936 · Cited by 56
“Adipose tissue (AT) iron overload is also closely related to macrophages, mainly reflected in the important role of macrophages in controlling iron metabolism (62).”
BackgroundWang, S., Shen, H., Mao, Q., Tao, Q., Yuan, G., Zeng, L., Chen, Z., Zhang, Y., Cheng, L., Zhang, J., et al. (2021) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.1c12406 · Cited by 51
F-box and leucine-rich repeat protein 5 (FBXL5): Sensing intracellular iron and oxygen
Ruiz, J. C., & Bruick, R. K. (2014) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2014.01.015 · Cited by 51
Haptoglobin increases the vulnerability of CD 163‐expressing neurons to hemoglobin
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Hemozoin produced by mammals confers heme tolerance
Pek, R. H., Yuan, X., Rietzschel, N., Zhang, J., Jackson, L. K., Nishibori, E., Ribeiro, A. C., Simmons, W. R., Jagadeesh, J., Sugimoto, H., et al. (2019) · eLife · doi:10.7554/elife.49503 · Cited by 51
“Heme-iron recycling of senescent erythrocytes occurs in the RES macrophages - mainly in the splenic RPMs and, to some extent, in liver Kupffer cells and bone marrow macrophages ( Beaumont and Delaby, 2009 ; Ganz, 2012 ; Theurl et al., 2016 ).”
BackgroundInfluentialStrategies of intracellular pathogens for obtaining iron from the environment
Leon-Sicairos, N., Reyes-Cortes, R., Guadrón-Llanos, A. M., Madueña-Molina, J., Leon-Sicairos, C., & Canizalez-Román, A. (2015) · BioMed Research International · doi:10.1155/2015/476534 · Cited by 51
“Alternatively, iron from endosomes or phagolysosomes may also be delivered by an unknown carrier to ferroportin (Fpn) for export [20].”
BackgroundPathways of iron acquisition and utilization in Leishmania
Flannery, A. R., Renberg, R. L., & Andrews, N. W. (2013) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.07.018 · Cited by 50
“Because of the extensive phagocytosis of senescent red blood cells performed by macrophages from deeper organs such as the spleen [42 ], markedly different levels of iron are expected to be available within skin macrophages where cutaneous species of Leishmania replicate, when compared to liver Kupffer cells and splee…”
BackgroundLasocki, S., Gaillard, T., & Rineau, E. (2014) · Critical Care · doi:10.1186/s13054-014-0678-7 · Cited by 50
“Using a model of acute lung injury secondary to peritonitis, Chen and colleagues show that the knockdown of hepcidin aggravates the acute lung injury (with increased mortality) probably through two main factors: an exacerbation of lung sepsis, thanks to an impaired phagocytic activity of alveolar macrophages (the redu…”
BackgroundHuman and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells
Meinderts, S. M., Oldenborg, P., Beuger, B. M., Klei, T. R. L., Johansson, J., Kuijpers, T. W., Matozaki, T., Huisman, E. J., de Haas, M., van den Berg, T. K., et al. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017004671 · Cited by 48
“In line with the current literature, we found that under steady-state conditions (in the absence of anti-RBC antibodies) macrophages are responsible for RBC clearance.(2,35) For IgG-opsonized RBCs, as in AIHA, the mechanism of RBC clearance appears different.”
MethodWoicke, J., Al-Haddawi, M., Bienvenu, J.-G., Rae, J. M. C., Chanut, F. J.-A., Colman, K., Cullen, J. M., Davis, W. P., Fukuda, R., Huisinga, M., et al. (2021) · Toxicologic Pathology · doi:10.1177/0192623320968181 · Cited by 45
“Erythrophagocytosis is an important physiologic process to recycle iron from senescent or damaged erythrocytes to extract heme.(54) In diseased animals, the severity of the process may be increased.”
BackgroundRAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease
Li, Y., Qin, M., Zhong, W., Liu, C., Deng, G., Yang, M., Li, J., Ye, H., Shi, H., Wu, C., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102559 · Cited by 45
“is exported from macrophages via FPN1, or stored intracellularly via ferritin [54,55].”
BackgroundTomay, F., Marinelli, A., Leoni, V., Caccia, C., Matros, A., Mock, H., Tonelli, C., & Petroni, K. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1972-6 · Cited by 48
Rodriguez, G. M., Sharma, N., Biswas, A., & Sharma, N. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.876667 · Cited by 47
“Macrophages are responsible for recycling iron from hemoglobin in senescent red blood cells (the largest iron pool in the host) and exporting it to satisfy systemic iron demand (Armstrong and Hart., 1975; Ganz, 2012).”
BackgroundImpaired iron recycling from erythrocytes is an early hallmark of aging
Slusarczyk, P., Mandal, P. K., Zurawska, G., Niklewicz, M., Chouhan, K., Mahadeva, R., Jończy, A., Macias, M., Szybińska, A., Cybulska, M., et al. (2023) · eLife · doi:10.7554/elife.79196 · Cited by 40
“To reduce the risk of RBC breakdown in the blood vessels and because mammals evolved under limited dietary iron availability, 90% of the body iron needs are met by internal iron recycling from aged RBCs ( Ganz, 2012 ).”
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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