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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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Identification SYT13 as a novel biomarker in lung adenocarcinoma
Zhang, L., Fan, B., Zheng, Y., Lou, Y., Cui, Y., Wang, K., Zhang, T., & Tan, X. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29224 · Cited by 24
“The availability of iron affects the production and secretion of cytokines, thereby modulating the macrophage phenotype.(21,22) All of these indicate the effects of intracellular biomolecule synthesis, transport, and secretion on the disease.”
BackgroundHybrid PET/MR imaging in myocardial inflammation post-myocardial infarction
Wilk, B., Wisenberg, G., Dharmakumar, R., Thiessen, J. D., Goldhawk, D. E., & Prato, F. S. (2019) · Journal of Nuclear Cardiology · doi:10.1007/s12350-019-01973-9 · Cited by 28
Iron Deposition and Ferroptosis in the Spleen in a Murine Model of Acute Radiation Syndrome
Rittase, W. B., Slaven, J. E., Suzuki, Y., Muir, J. M., Lee, S., Rusnak, M., Brehm, G. V., Bradfield, D. T., Symes, A. J., & Day, R. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911029 · Cited by 23
“Iron regulates iron binding and transport proteins in macrophages and modulates macrophage polarity [17,48,49].”
BackgroundWinn, N. C., Wolf, E. M., Cottam, M. A., Bhanot, M., & Hasty, A. H. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00116.2021 · Cited by 21
Cellular Immune Signal Exchange From Ischemic Stroke to Intestinal Lesions Through Brain-Gut Axis
Yang, Z., Wei, F., Zhang, B., Luo, Y., Xing, X., Wang, M., Chen, R., Sun, G., & Sun, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.688619 · Cited by 26
“Such signals will drive the decrease of inducible nitric oxide synthase (iNOS) and the increase of arginase-1 (Arg-1), which could break the Arginine metabolism’s balance, or lead to nitric oxide (NO) creation (40, 41).”
BackgroundBadran, O., Cohen, I., & Bar‐Sela, G. (2024) · Cancers · doi:10.3390/cancers16244156 · Cited by 26
Nitric oxide pathway-related gene alterations in inflammatory bowel disease
Gillberg, L., Varsanyi, M., Sjöström, M., Lördal, M., Lindholm, J., & Hellström, P. M. (2012) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2012.706830 · Cited by 22
“However, M1 macrophages have lower expression of the transferrin receptor as an attempt to withhold iron from invading pathogens [53,54].”
BackgroundZordan, P., Sciorati, C., Campana, L., Cottone, L., Clementi, E., Querini, P.-R., & Brunelli, S. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.05.007 · Cited by 24
“Interestingly after 4 months of molsidomine administration, most macrophages expressed both markers that are conventionally associated to classically and to alternatively activated macrophages (CD206+CD163+CD86+).”
BackgroundInfluentialSelf-citationAgoro, R., Benmerzoug, S., Rose, S., Bouyer, M., Gozzelino, R., Garcia, I., Ryffel, B., Quesniaux, V. F. J., & Mura, C. (2017) · The Journal of Infectious Diseases · doi:10.1093/infdis/jix366 · Cited by 22
Satoh, J. (2017) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12426 · Cited by 22
“Trfc is expressed at high levels on M2 macrophages, possibly serving as a novel M2a marker.(35) These results suggest that M2a-polarizing conditions, which upregulate non-redundant 94 genes, are less effective for induction of genes in three distinct microglia than M1-polarizing conditions that upregulate 1202 non-red…”
BackgroundAccumulation of Intracellular Ferrous Iron in Inflammatory-Activated Macrophages
Ma, H., Shu, Q., Li, D., Wang, T., Li, L., Song, X., Lou, K., & Xu, H. (2022) · Biological Trace Element Research · doi:10.1007/s12011-022-03362-9 · Cited by 24
“1 3 the polarization of macrophages towards the inflammatory activation [9, 10].”
BackgroundChen, Q., Zheng, Y., Chen, X., Xing, Y., Zhang, J., Yan, X., Zhang, Q., Wu, D., & Chen, Z. (2024) · Advanced Science · doi:10.1002/advs.202308124 · Cited by 21
Singh, N. K., Bajpai, S., Kumar, V., Gour, J. K., & Singh, R. K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053442 · Cited by 21
“The labile iron pool (LIP) is redox-active chelatable iron in cytosolic compartment of the cells, which can be directly determined by various fluorescent iron probes [31,32].”
BackgroundBenasciutti, E., Mariani, E., Oliva, L., Scolari, M. P., Perilli, E., Barras, E., Milan, E., Orfanelli, U., Fazzalari, N. L., Campana, L., et al. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2090 · Cited by 23
“Polarized macrophages were generated as described.((20)) Briefly, after 7 days of culture in a‐MEM (Life Technologies) containing 10% FCS (Lonza, Basel, Switzerland) in the presence of 100 ng/mL M‐CSF, BMM from C57BL/6 female mice were differentiated in inflammatory (M1) or immunoregulatory (M2) macrophages, culturing…”
MethodSelf-citationFerritin as an Effective Prognostic Factor and Potential Cancer Biomarker
Szymulewska-Konopko, K., Reszeć-Giełażyn, J., & Małeczek, M. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47010060 · Cited by 27
“Furthermore, hypoxia is a key regulator of various genes in growing tumors, which may affect hepcidin expression [52,53].”
Guggisberg, C. A., Kim, J.-Y., Lee, J., Chen, X., & Ryu, M. (2022) · Antioxidants · doi:10.3390/antiox11101926 · Cited by 20
“The enhanced production of ferritin by inflammatory stimuli have been demonstrated to be driven primarily by increasing ferritin H expression rather than that of ferritin L [26,40,41].”
BackgroundAsthma as a disruption in iron homeostasis
Ghio, A. J. (2016) · BioMetals · doi:10.1007/s10534-016-9948-y · Cited by 21
An Iron Refractory Phenotype in Obese Adipose Tissue Macrophages Leads to Adipocyte Iron Overload
Ameka, M., Beavers, W. N., Shaver, C. M., Ware, L. B., Kerchberger, V. E., Schoenfelt, K. Q., Sun, L., Koyama, T., Skaar, E. P., Becker, L., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137417 · Cited by 20
Reprogramming of pancreatic adenocarcinoma immunosurveillance by a microbial probiotic siderophore
Chaib, M., Hafeez, B. B., Mandil, H., Daria, D., Pingili, A. K., Kumari, S., Sikander, M., Kashyap, V. K., Chen, G., Anning, E., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-04102-4 · Cited by 20
dECM restores macrophage immune homeostasis and alleviates iron overload to promote DTPI healing
Ju, Z., Si, R., Gao, Y., Shan, H., Su, Q., Feng, Z., Huang, P., Kong, D., & Wang, W. (2024) · Regenerative Biomaterials · doi:10.1093/rb/rbad118 · Cited by 19
“An iron release can promote the growth of neighboring cells and the repair of tissues [13].”
BackgroundMathematical model of mycobacterium–host interaction describes physiology of persistence
Pedruzzi, G., Rao, K. V. S., & Chatterjee, S. (2015) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2015.03.031 · Cited by 21
Song, X., Wang, Z., Tian, Z., Wu, M., Zhou, Y., & Zhang, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076399 · Cited by 18
“Despite a significant amount of literature suggesting the involvement of ferroptosis in the pathogenesis of MS, its specific role in the etiology of the disease remains unclear [15,16].”
BackgroundMehrabian, Z., Guo, Y., Weinreich, D. M., & Bernstein, S. L. (2017) · PubMed Central · Cited by 18
Microglial iron trafficking: new player in brain injury
Keleş, E., Kazan, H. H., Aral, A., & BELEN, H. B. (2022) · TURKISH JOURNAL OF MEDICAL SCIENCES · doi:10.55730/1300-0144.5481 · Cited by 17
“M1 macrophages respond to extracellular iron imbalance or overload with a limited capacity [51, 65, 66].”
BackgroundParreau, S., Molina, E., Dumonteil, S., Goulabchand, R., Naves, T., Bois, M. C., Akil, H., Terro, F., Fauchais, A. L., Liozon, É., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1237986 · Cited by 17
Iron scavenging and myeloid cell polarization
Ludwig, N., Cucinelli, S., Hametner, S., Muckenthaler, M. U., & Schirmer, L. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.06.006 · Cited by 16
Macrophage Metabolic Reprogramming in Inflammatory Bowel Diseases: From Pathogenesis to Therapy
Zhang, Y.-F., Shi, T. T., Lin, Y., Zhu, Y., Lin, S., & Fang, T. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s534447 · Cited by 19
“135 Iron overload increases reactive oxygen species (ROS) and hepcidin levels, promoting M1 macrophage polarization by inducing p53 acetylation and 4E-BP1 phosphorylation.”
Sharawy, N., Imam, A. A.-A., Aboulhoda, B. E., Khalifa, M. M., Morcos, G. N. B., Algaleel, W. A. A., Moustafa, P. E., Elbaset, M. A., & Shoukry, T. M. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.953206 · Cited by 16
“Moreover, in vitro studies revealed that the alteration of the cellular iron balance may be a consequence of macrophage polarization (Corna et al., 2010; Recalcati et al., 2019).”
BackgroundWang, Z., Liu, T., Wang, Z., Mi, Z., Zhang, Y., Wang, C., Sun, L., Ma, S., Xue, X., Liu, H., et al. (2023) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2023.10.012 · Cited by 16
Pang, N., Ding, M., Hu, Y., Zhong, Q., Zheng, L., Luo, D., & Yao, Y. (2023) · Haemophilia · doi:10.1111/hae.14905 · Cited by 16
“21 In the synovial membrane, macrophages are the cells that respond rapidly to stimuli and transform into a specific functionalphenotypeinaprocesscalledpolarization.”
BackgroundPease, N. A., Shephard, M. S., Sertorio, M. G., Waltz, S. E., & Vinnedge, L. M. P. (2020) · Cancers · doi:10.3390/cancers12071936 · Cited by 16
“An iron recycling phenotype in TAMs is important because this provides an increased concentration of iron in the microenvironment to support the metabolic demands of rapidly proliferating tumor cells [65,69].”
BackgroundForming Magnetosome-Like Nanoparticles in Mammalian Cells for Molecular MRI
Goldhawk, D. E., Gelman, N., Thompson, R. T., & Prato, F. S. (2016) · Springer eBooks · doi:10.1007/978-3-319-42169-8_9 · Cited by 15
Macrophages play a role in inflammatory transformation of colorectal cancer
Lu, L., Liu, Y.-J., Cheng, P., Hu, D., Xu, H.-C., & Ji, G. (2021) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v13.i12.2013 · Cited by 16
Swaminathan, S., Bose, C., Shah, S. V., Hall, K. A., & Hiatt, K. M. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.06.008 · Cited by 16
Nicolosi, P. A., Tombetti, E., Giovenzana, A., Donè, E., Pulcinelli, E., Meneveri, R., Tirone, M., Maugeri, N., Rovere, P. Q., Manfredi, A. A., et al. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1800883 · Cited by 15
“Bone marrow cells from flushed femurs and tibias of C57BL/6 female mice were propagated for 5 d in a-modified Eagle’s medium (a-MEM) (Life Technologies/Invitrogen, Carlsbad, CA) containing FBS (10%) in presence of recombinant mouse (rm) M-CSF (100 ng/ml) (30).”
MethodSelf-citationMacrophages: friend or foe in diabetes pathogenesis and therapy
Grimes, R. N., Orecchioni, M., & Quesada‐Masachs, E. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1625391 · Cited by 15
Balounová, J., Vavrochová, T., Benešová, M., Ballek, O., Kolář, M., & Filipp, D. (2014) · European Journal of Immunology · doi:10.1002/eji.201344040 · Cited by 13
Phenylbutyrate facilitates homeostasis of non-resolving inflammatory macrophages
Rahtes, A., Pradhan, K., Sarma, M., Xie, D., Lu, C., & Li, L. (2019) · Innate Immunity · doi:10.1177/1753425919879503 · Cited by 16
“Further, up-regulation of FPN has been associated with alternatively activated anti-inflammatory M2-like polarized macrophages.(26,27) Thus, further analysis of the connection between these factors (p62, Nrf2, and FPN) may provide a better understanding of the coupled intracellular circuitry responsible for macrophage…”
BackgroundThe Role of Copper in the Regulation of Ferroportin Expression in Macrophages
Jończy, A., Mazgaj, R., Smuda, E., Żelazowska, B., Kopeć, Z., Starzyński, R. R., & Lipiński, P. (2021) · Cells · doi:10.3390/cells10092259 · Cited by 18
“The M1/M2 macrophage phenotype impacts Fpn levels, where Fpn was downregulated in M1 and upregulated in M2 macrophages [58,59].”
Background
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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