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).
“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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“Macrophages are an essential component of iron homeostasis [50], and are probably involved in the process, either by capturing SPIONs in the MPS and/or by specialising in physiological regulation of iron (Kupffer cells in liver or metallophilic macrophages in spleen).”
BackgroundMacrophages and Iron Metabolism
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Self-citationRole of iron in the pathogenesis of respiratory disease
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“…play a principal role in maintaining iron homeostasis through the sequestration of haem-iron from senescent RBCs for storage and recycling, the uptake and storage of TF-bound iron and, in the lung, the clearance of inhaled iron-containing particulate matter (Gammella, 2014; Ganz, 2012) (Fig 1 & 2).”
BackgroundDevelopment and function of tissue resident macrophages in mice
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“As professional scavenging cells, macrophages are critically involved in systemic iron homeostasis through ingestion and degradation of senescent/ damaged erythrocytes for iron recovery from hemoglobin and iron-containing enzymes [39].”
BackgroundChronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes
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“The most abundant type of macrophage is the red pulp macrophage, characterized by expression of CD163, which is thought to be involved in the clearance of aged red blood cells from the circulation and iron metabolism.(11,13) The open circulation of the red pulp functions as a filter for blood, resulting in close conta…”
Background‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease
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Activation of the NLRP3 inflammasome by cellular labile iron
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Iron Homeostasis in the Lungs—A Balance between Health and Disease
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“Most of the iron required to sustain the body’s metabolic needs is provided by reticuloendothelial macrophages that recycle iron from senescent RBCs [5].”
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“Using their scavenger receptor repertoire, KCs are involved in the clearance of apoptotic cell debris and central to iron homeostasis (71).”
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“(E3) The effects of PS and CD47 cancel out each other [40], so that the net balance between PS and CD47 in an RBC determines whether or not it is destroyed by macrophages [22].”
BackgroundIron homeostasis: a new job for macrophages in adipose tissue?
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Nanoparticle-Based Magnetic Resonance Imaging on Tumor-Associated Macrophages and Inflammation
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“Indeed, the macrophages are trained to maintain endogenous iron homeostasis while recycling and storing iron from senescent erythrocytes and other damaged cells (44, 45).”
BackgroundTime-course assessment of the aggregation and metabolization of magnetic nanoparticles
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“Unless it is not required, the metal exits the macrophages thanks to the SLC40A1, is oxidized by ceruloplasmin and bound to Tf, thus subsequently replenishing most of the Tf iron pool [26].”
BackgroundAge-Related Changes and Sex-Related Differences in Brain Iron Metabolism
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“Erythropoietin reduces iron retention in macrophages by decreasing DMT1 and increasing FPN1 expression [72].”
BackgroundInfluentialIron acquisition strategies in mycobacteria
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“Erythrocytes are degraded in the phagosomes of macrophages resulting in heme release [38,39], exposing M.”
BackgroundHigh Fat Diet Subverts Hepatocellular Iron Uptake Determining Dysmetabolic Iron Overload
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“Facilitation of hepatic iron accumulation was not explained by decreased hepcidin nor by reduced expression of Fp-1, which was not downregulated by hepcidin possibly due to the balanced effect of inflammation, increased hepcidin and hepatocellular iron stores [22,33], or a possible state of hepcidin resistance in spec…”
BackgroundRole of macrophages in experimental liver injury and repair in mice (Review)
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Friend or Foe? Recent Strategies to Target Myeloid Cells in Cancer
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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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BackgroundIron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores
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“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).”
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The Multiple Facets of Iron Recycling
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Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling
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Hemolysis and immune regulation
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Diversity and environmental adaptation of phagocytic cell metabolism
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“1 Introduction Approximately 2 × 1011 RBCs are synthesized each day in the healthy adult human (1, 2).”
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The intricate role of selenium and selenoproteins in erythropoiesis
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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).”
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“Adipose tissue (AT) iron overload is also closely related to macrophages, mainly reflected in the important role of macrophages in controlling iron metabolism (62).”
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Haptoglobin increases the vulnerability of CD 163‐expressing neurons to hemoglobin
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Hemozoin produced by mammals confers heme tolerance
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“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
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BackgroundPathways of iron acquisition and utilization in Leishmania
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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 · see citing works
“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.”
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“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
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“is exported from macrophages via FPN1, or stored intracellularly via ferritin [54,55].”
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“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 · see citing works
“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 ).”
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Physical Sciences › Engineering › Mechanical Engineering › 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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