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Polarization dictates iron handling by inflammatory and alternatively activated macrophages
Open accessAbstract
BACKGROUND: Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes. DESIGN AND METHODS: Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells. RESULTS: M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize--albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective. CONCLUSIONS: Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).
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“tumour-associated macrophages may promote iron release in the tumour microenvironments40,41.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [40]
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BackgroundShan, H., Dou, W., Zhang, Y., & Qi, M. (2020) · Nanoscale · doi:10.1039/d0nr04520a · Cited by 93
Liver X Receptor Activation Stimulates Iron Export in Human Alternative Macrophages
Bories, G. F. P., Colin, S., Vanhoutte, J., Derudas, B., Copin, C., Fanchon, M., Daoudi, M., Belloy, L., Haulon, S., Zawadzki, C., et al. (2013) · Circulation Research · doi:10.1161/circresaha.113.301656 · Cited by 101
“This observation is in agreement with previous results obtained in human and mouse alternative macrophages differentiated in the presence of M-CSF and IL-4 for 2 days.(30,31) Interestingly, we found that M2 macrophages also phagocytose erythrocytes more avidly compared with RM macrophages.”
ResultSciorati, C., Clementi, E., Manfredi, A. A., & Rovere, P. Q. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1857-7 · Cited by 99
“tightly dependent on their polarization state [202] and that might play a role in the effective regeneration of the tissue (G.”
BackgroundSelf-citationLepanto, M. S., Rosa, L., Cutone, A., Conte, M. P., Paesano, R., & Valenti, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02123 · Cited by 91
“Indeed, upon inflammatory stimulation, macrophages polarize in a subpopulation, namely M1, characterized by production of proinflammatory cytokines, such as IL-6, the down-regulation of Fpn and up-regulation of cytosolic Ftn, leading to the block of iron recycling to blood from senescent erythrocytes, the major iron s…”
BackgroundThe Multifaceted Role of Macrophages in Biology and Diseases
Brancewicz, J., Wójcik, N., Sarnowska, Z., Robak, J., & Król, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052107 · Cited by 103
“For example, studies in murine models of wound healing have demonstrated that macrophage-derived iron is critical for the proliferation of keratinocytes and the formation of granulation tissue [36,39].”
Local iron homeostasis in the breast ductal carcinoma microenvironment
Marques, O., Porto, G., Rêma, A., Faria, F., Cruz Paula, A., Gomez-Lazaro, M., Silva, P., Martins da Silva, B., & Lopes, C. (2016) · BMC Cancer · doi:10.1186/s12885-016-2228-y · Cited by 90
“Of note, in vitro M2 polarized macrophages present an iron-release prone phenotype, with higher transferrin receptor 1 and ferroportin 1 expression than classically activated M1 macrophages, which is thought to contribute to its iron recycling function as scavengers of senescent and apoptotic cells and in tissue remod…”
BackgroundRegenerative inflammation: When immune cells help to re‐build tissues
Caballero‐Sánchez, N., Alonso‐Alonso, S., & Nagy, L. (2022) · FEBS Journal · doi:10.1111/febs.16693 · Cited by 100
“While pro-inflammatory M1 macrophages are associated with glycolytic metabolism and impaired mitochondrial oxidative phosphorylation (OXPHOS), M2s are characterized by an upregulation of genes involved in glutamine metabolism, associated with OXPHOS [102] and the secretion of iron [103].”
Background‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease
Nairz, M., Schroll, A., Demetz, E., Tancevski, I., Theurl, I., & Weiss, G. (2015) · Immunobiology · doi:10.1016/j.imbio.2014.09.010 · Cited by 89
Jézéquel, P., Campion, L., Spyratos, F., Loussouarn, D., Campone, M., Guérin‐Charbonnel, C., Joalland, M., André, J., Descotes, F., Grenot, C., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.26397 · Cited by 85
“CD86 and CD163 antibodies were used to discriminate between M2 macrophages (CD86 low and CD163 high) and M1 (CD86 high and CD163 intermediate).(20,22) In our study, TAM population exhibited a low level of CD86[IHC] (0.”
MethodBosurgi, L., Manfredi, A. A., & Rovere, P. Q. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00062 · Cited by 87
“…immune responses even in the context of sterile injuries (Bianchi, 2007; Lotze et al., 2007; Rubartelli and Lotze, 2007; Urbonaviciute et al., 2008; Bianchi and Manfredi,2009; Manfredi and Rovere-Querini, 2010; Maroso et al., 2010; Castiglioni et al., 2011; Liu et al., 2011b; Zhang et al., 2011).”
BackgroundSelf-citationIntravenous Irons: From Basic Science to Clinical Practice
Bhandari, S., Pereira, D. I. A., Chappell, H. F., & Drakesmith, H. (2018) · Pharmaceuticals · doi:10.3390/ph11030082 · Cited by 88
“This is an area of current interest—IV iron metabolism is likely to vary depending on the type and differentiation state of the macrophage processing the iron [44,45], and iron itself can alter macrophage polarisation [46], so that the different characteristics of each iron-carbohydrate complex may potentially affect…”
BackgroundMertens, C., Akam, E. A., Rehwald, C., Brüne, B., Tomat, E., & Jung, M. (2016) · PLOS ONE · doi:10.1371/journal.pone.0166164 · Cited by 83
Lack of iron, zinc, and vitamins as a contributor to the etiology of atopic diseases
Peroni, D. G., Hufnagl, K., Comberiati, P., & Roth‐Walter, F. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2022.1032481 · Cited by 87
“Pro-inflammatory M1 macrophages neither partake in iron sequestration nor export, and intracellularly their labile and metabolic active iron levels are low, as the available iron is entrapped within ferritin, making it inaccessible for pathogens, but also nutritional supply (92).”
BackgroundHigh-Dose Vitamin C for Cancer Therapy
Mussa, A., Idris, R. A. M., Ahmed, N., Ahmad, S., Murtadha, A. H., Din, T. A. D. A. T., Yean, C. Y., Rahman, W. F. W. A., Lazim, N. M., Uskoković, V., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15060711 · Cited by 85
“Furthermore, macrophages in the cancer microenvironment have been revealed to increase iron shedding [96,97].”
BackgroundIron homeostasis: a new job for macrophages in adipose tissue?
Hubler, M. J., Peterson, K. R., & Hasty, A. H. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.12.005 · Cited by 79
Joffin, N., Gliniak, C. M., Funcke, J., Paschoal, V. A., Crewe, C., Chen, S., Gordillo, R., Kusminski, C. M., Oh, D. Y., Geldenhuys, W. J., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00664-z · Cited by 79
Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells
Liang, W. P., & Ferrara, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.626812 · Cited by 75
“M2 macrophages, on the other hand, show low expression of ferritin and high expression of ferroportin, representing an iron-releasing phenotype (39, 40).”
BackgroundBabu, M., Devi, T. D., Mäkinen, P., Kaikkonen, M. U., Lesch, H. P., Junttila, S., Laiho, A., Ghimire, B. R., Gyenesei, A., & Ylä‐Herttuala, S. (2015) · Circulation Research · doi:10.1161/circresaha.115.306424 · Cited by 74
Wang, B., Zhang, W., Zhou, X., Liu, M., Hou, X., Cheng, Z., & Chen, D. (2019) · Drug Delivery · doi:10.1080/10717544.2019.1693707 · Cited by 74
“Furthermore, transferrin receptor, legumain and folate receptor beta are also three other targeted receptors overexpressed on M2TAMs (Wenyuan, 2006; Amaya, 2009; Gianfranca, 2010; Yoshiyuki et al., 2015).”
BackgroundZordan, P., Rigamonti, E., Freudenberg, K., Conti, V., Azzoni, E., Rovere, P. Q., & Brunelli, S. (2014) · Cell Death and Disease · doi:10.1038/cddis.2013.558 · Cited by 74
Self-citationThe Repair of Skeletal Muscle Requires Iron Recycling through Macrophage Ferroportin
Corna, G., Caserta, I., Monno, A., Apostoli, P., Manfredi, A. A., Camaschella, C., & Rovere-Querini, P. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501417 · Cited by 63
“Bone marrow precursors from C57BL/6 female mice were isolated and propagated for 7 d in anti-MEM (Life Technologies, Invitrogen) containing 10% FBS (Lonza) in the presence of recombinant murine (rm)M-CSF (100 ng/ml; Miltenyi Biotec) to generate macrophages as described previously (7).”
MethodSelf-citationRegenerative Capacity of Macrophages for Remyelination
Rawji, K. S., Mishra, M. K., & Yong, V. W. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00047 · Cited by 70
Temporal phenotypic features distinguish polarized macrophagesin vitro
Melton, D. W., McManus, L. M., Gelfond, J., & Shireman, P. K. (2015) · Autoimmunity · doi:10.3109/08916934.2015.1027816 · Cited by 65
di Patti, M. C. B., Cutone, A., Polticelli, F., Rosa, L., Lepanto, M. S., Valenti, P., & Musci, G. (2018) · BioMetals · doi:10.1007/s10534-018-0087-5 · Cited by 66
“While it has been reported that macrophages can express different ‘‘iron-retention’’ or ‘‘iron-release’’ phenotypes (Recalcati et al. 2010; Corna et al. 2010), we have shown that under conditions where an ‘‘iron retention’’ phenotype is achieved, bLf affects the expression of Fpn, TfR1, Ftn, and Cp-GPI, counteracting…”
Cutone, A., Frioni, A., Berlutti, F., Valenti, P., Musci, G., & di Patti, M. C. B. (2014) · BioMetals · doi:10.1007/s10534-014-9742-7 · Cited by 64
“Different groups have reported that in vitro polarized murine and human M1 inflammatory macrophages present a ‘storage’ phenotype while M2 tolerogenic macrophages have effective iron-recycling capacity (Corna et al. 2010; Recalcati et al. 2010).”
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
“In contrast, M1 macrophages do not partake in iron sequestration, although they favor an iron storage phenotype having a low LIP, increased ferritin-levels and decreased FPN expression (Figure 2) (126, 137, 138).”
BackgroundYang, H., Lin, M., Korivi, M., Wu, J., Liao, C.-H., Chang, C., Liao, J., & Hseu, Y. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.11.001 · Cited by 62
Macrophage ferroportin is essential for stromal cell proliferation in wound healing
Recalcati, S., Gammella, E., Buratti, P., Doni, A., Anselmo, A., Locati, M., & Cairo, G. (2018) · Haematologica · doi:10.3324/haematol.2018.197517 · Cited by 68
Lipocalin-2 and iron trafficking in the tumor microenvironment
Jung, M., Mertens, C., Bauer, R., Rehwald, C., & Brüne, B. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.03.018 · Cited by 63
Linking 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
Iron gene expression profile in atherogenic Mox macrophages
Marques, L., Nègre‐Salvayre, A., Costa, L. M. G., & Canonne‐Hergaux, F. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.03.004 · Cited by 62
Rosito, M., Testi, C., Parisi, G., Cortese, B., Baiocco, P., & Angelantonio, S. D. (2020) · Antioxidants · doi:10.3390/antiox9080700 · Cited by 61
Iron homeostasis and anemia markers in early breast cancer
Lamy, P., Durigova, A., & Jacot, W. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.04.011 · Cited by 60
Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells
Wang, P., & Lu, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.877634 · Cited by 57
“M1 phenotype expresses high levels of ferritin, divalent metal transporter 1 (DMT1), and hypoxia-inducible factor 1a (HIF1a), but expresses low levels of transferrin receptor and FPN to maximize iron absorption and storage, and down-regulate iron output (49).”
BackgroundMolecular regulation of cellular iron balance
Recalcati, S., Gammella, E., Buratti, P., & Cairo, G. (2017) · IUBMB Life · doi:10.1002/iub.1628 · Cited by 55
“Indeed, studies in human (82) and mouse (83) macrophages showed that FPN levels are low in M1 proinflammatory cells and high in M2 macrophages endowed with anti-inflammatory and tissue remodeling functions, in line with the iron sequestering and iron recycling phenotypes, respectively, of these two polarized populatio…”
BackgroundIkeda, Y., Watanabe, H., Shiuchi, T., Hamano, H., Horinouchi, Y., Imanishi, M., Goda, M., Zamami, Y., Takechi, K., Izawa-Ishizawa, Y., et al. (2020) · Diabetologia · doi:10.1007/s00125-020-05153-0 · Cited by 53
Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions
Zinger, N., Ponath, G., Sweeney, E., Nguyen, T. D., Lo, C. H., Diaz, I., Dimov, A., Teng, L., Zexter, L., Comunale, J., et al. (2022) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001138 · Cited by 51
“states.(16,18) Here, we demonstrated that iron uptake is increased in M1-polarized compared with M0- and M2-polarized human iPSC-derived microglia and that treatment with DMF reduced proinflammatory activation in M1-polarized microglia and increases iron release.”
Wu, S.-Y., Huang, J.-H., Chen, W.-Y., Chan, Y., Lin, C., Chen, Y., Liu, F., & Wu‐Hsieh, B. A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00048 · Cited by 53
“Consistent with previous findings (47, 48), we found that gal3 plays a positive role in activation of M2 macrophage marked by lower MHC II and higher CD206 expression.”
ResultFerroptosis 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
“Studies have shown that obesity induces increased M1macrophages (M1) polarization in mice, which may further promote iron deposition, according to in vitro studies (63).”
Backgroundde Oliveira, J., Denadai, M. B., & Costa, D. L. (2022) · Antioxidants · doi:10.3390/antiox11050861 · Cited by 54
Metadata
- Authors
- Corna, G., Campana, L., Pignatti, E., Castiglioni, A., Tagliafico, E., Bosurgi, L., Campanella, A., Brunelli, S., Manfredi, A. A., Apostoli, P., Silvestri, L., Camaschella, C., & Rovere-Querini, P.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- University of Modena and Reggio Emilia (IT)
- IRCCS Ospedale San Raffaele (IT)
- University of Brescia (IT)
- ORCID
- Venue
- Haematologica
- Published
- 2010-05-29
- Volume
- 95
- Issue
- 11
- Pages
- 1814-1822
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC2966902
- OpenAlex
- W2096008021
- Cited by
- 304
- References
- 47
- Citations by year
- 2026: 21 · 2025: 12 · 2024: 25 · 2023: 17 · 2022: 32 · 2021: 23 · 2020: 13 · 2019: 20 · 2018: 22 · 2017: 23 · 2016: 18 · 2015: 14 · 2014: 17 · 2013: 22 · 2012: 15
- FWCI
- 9.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Fondazione Cariplo
- Ministero della Salute
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- macrophage polarization, iron homeostasis, M1 macrophages, M2 macrophages, iron recycling, H-ferritin, transferrin receptor 1, ferroportin, iron regulatory proteins, labile iron pool, interferon-gamma, IL-4, T cell activation
- MeSH terms
- Ferroportin, Animals, Apoferritins, Gene Expression Regulation, Inflammation, Interferon-gamma, Iron, Lymphocyte Activation, Macrophage Activation, Macrophages, Receptors, Transferrin, T-Lymphocytes, Interleukin-4, Cation Transport Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice
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