Iron levels in polarized macrophages: regulation of immunity and autoimmunity
Abstract
Although the hallmark of autoimmune diseases remains the generation of autoantigen-specific lynfocytic cell response, growing evidence is showing a key role for macrophages in a number of autoimmune diseases. Macrophages are characterized by phenotypical and functional heterogeneity. Different immunological signals, coming from systemic blood circulation or from microenvironment, polarize macrophages to classical (M1) or alternative (M2) phenotypes. Iron accumulation in M1 macrophages is a well known bacteriostatic mechanism and one of the mechanisms at the basis of anemia associated to chronic inflammation. Moreover, some recent data suggest that iron accumulation in macrophages can directly activate macrophages to pro-inflammatory M1 phenotype, highlighting a putative role of macrophage iron retention in the pathogenesis of chronic inflammatory and autoimmune diseases. Conversely, iron content is low in M2 macrophages, principally due to increased iron release, and increased availability of iron in the extracellular milieu supported by M2 macrophages could influence the growth rate of adjacent cell and thus play an important role in tumor growth and tissue remodeling. In this review we summarize the molecular mechanisms sustaining differential iron metabolism in polarized macrophages, discuss the relevance of this metabolic signature in chronic inflammatory and autoimmune diseases, and finally focus on potential therapeutic implications rising from a better understanding of underlying molecular mechanisms.
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The intracellular iron equilibrium can regulate the polarization of macrophages into M1 (pro-inflammatory) and M2 (anti-inflammatory, pro-tissue healing) macrophages depending on their micro-environmental niche and local metabolic cues.
“The intracellular iron equilibrium can regulate the polarization of macrophages into M1 (pro-inflammatory) and M2 (anti-inflammatory, pro-tissue healing) macrophages depending on their micro-environmental niche and local metabolic cues (Recalcati et al., 2012).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Recalcati et al., 2012
Regulation of macrophage intracellular iron content by the hepcidin/FPN axis impacts macrophage polarization and presumably resistance to infection.
“Regulation of Mø intracellular Fe content by the hepcidin/FPN axis impacts on Mø polarization and presumably therefore resistance to infection [6,66,67].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [67]
This defense strategy changes cellular iron content, which affects the microbicidal activity of innate immune cells such as macrophages.
“Importantly, this defense strategy modulates cellular Fe content, which impacts on the microbicidal activity of innate immune cells such as macrophages (30, 98, 99).”
From Innate Nutritional Immunity (2018) · cites this paper as [99]
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Splenic Macrophage Subsets and Their Function during Blood-Borne Infections
da Silva, H. B., Fonseca, R., Pereira, R. M., Cassado, A. D. A., Álvarez, J. M., & Lima, M. R. D. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00480 · Cited by 202 · see citing works
Metformin and Autoimmunity: A “New Deal” of an Old Drug
Ursini, F., Russo, E., Pellino, G., D’Angelo, S., Chiaravalloti, A., Sarro, G. D., Manfredini, R., & GIORGIO, R. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01236 · Cited by 195 · see citing works
“, the pro-inflammatory “classically” activated (M1) and the “alternatively” activated (M2, further subclassified as M2a, b, or c), mainly associated with resolution of inflammation and tissue repair processes (74, 75).”
BackgroundJiang, H.-J., Li, J., Wang, L., Wang, S.-J., Nie, X., Chen, Y., Fu, Q., Jiang, M.-Y., Fu, C., & He, Y. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.112913 · Cited by 158 · see citing works
Iron induces anti-tumor activity in tumor-associated macrophages
Costa da Silva, M., Breckwoldt, M. O., Vinchi, F., Correia, M. P., Stojanovic, A., Thielmann, C. M., Meister, M., Muley, T., Warth, A., Platten, M., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01479 · Cited by 164 · see citing works
“This supports the idea that exposure of TAMs to hemolytic RBCs and subsequent iron retention, which promotes their inflammatory phenotype, impacts on tumor cell viability (28, 57).”
BackgroundQuirós-Roldán, E., Biasiotto, G., Magro, P., & Zanella, I. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104904 · Cited by 153 · see citing works
Andersen, H. H., Johnsen, K. B., & Moos, T. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1509-8 · Cited by 151 · see citing works
“, via DMT1, M2 macrophages are characterized by a much lower iron content due to continuous release of iron through the iron-exporter ferroportin [44, 45].”
BackgroundAnaemia in inflammatory rheumatic diseases
Weiss, G., & Schett, G. (2013) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.183 · Cited by 146 · see citing works
Calderón‐Garcidueñas, L., Vojdani, A., Blaurock-Busch, E., Busch, Y. M., Friedle, A., Franco-Lira, M., Mukherjee, P. S., Martínez-Aguirre, X., Park, S., Torres‐Jardón, R., et al. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141365 · Cited by 143 · see citing works
“Immunomodulation of innate and adaptive immunity by metals, including metallic nanoparticles has been described in the literature [115-121].”
SPION primes THP1 derived M2 macrophages towards M1-like macrophages
Laskar, A., Eilertsen, J., Li, W., & Yuan, X.-M. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.10.115 · Cited by 138 · see citing works
Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions
Popescu, B. F. G., Frischer, J. M., Webb, S. M., Tham, M., Adiele, R. C., Robinson, C. A., Fitz‐Gibbon, P. D., Weigand, S. D., Metz, I., Nehzati, S., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1696-8 · Cited by 138 · see citing works
“Alternatively, the variable presence of iron rims may reflect differences in macrophage polarization [55] or changes in macrophage polarization as a result of iron loading [39].”
Iron Reduces M1 Macrophage Polarization in RAW264.7 Macrophages Associated with Inhibition of STAT1
Gan, Z.-S., Wang, Q., Li, J., Wang, X., Wang, Y., & Du, H. (2017) · Mediators of Inflammation · doi:10.1155/2017/8570818 · Cited by 127 · see citing works
“On the one hand, the polarization of macrophages can have important effects on ironmetabolism, but on the other hand iron can influence directly macrophage polarization [18].”
BackgroundNúñez, G., Sakamoto, K., & Soares, M. P. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800325 · Cited by 115 · see citing works
The Role of Macrophage Iron Overload and Ferroptosis in Atherosclerosis
Ma, J., Zhang, H., Chen, Y., Liu, X., Tian, J., & Shen, W. (2022) · Biomolecules · doi:10.3390/biom12111702 · Cited by 115 · see citing works
The role of hepcidin and iron homeostasis in atherosclerosis
Wunderer, F., Traeger, L., Sigurslid, H. H., Meybohm, P., Bloch, D. B., & Malhotra, R. K. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104664 · Cited by 107 · see citing works
The “Iron”-y of Iron Overload and Iron Deficiency in Chronic Obstructive Pulmonary Disease
Cloonan, S. M., Mumby, S. E., Adcock, I. M., Choi, A. M. K., Chung, K. F., & Quinlan, G. J. (2017) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201702-0311pp · Cited by 109 · see citing works
“Iron-regulatory responses differ between these phenotypes: M1 cells accumulate iron as part of a bacteriostatic stratagem linked to the anemia of chronic inflammation, whereas the opposite is the case for M2 cells, where iron release is favored (48).”
BackgroundStijlemans, B., BAETSELIER, P. D., Magez, S., Ginderachter, J. A. V., & Trez, C. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00218 · Cited by 101 · see citing works
Macrophages: central regulators of iron balance
Gammella, E., Buratti, P., Cairo, G., & Recalcati, S. (2014) · Metallomics · doi:10.1039/c4mt00104d · Cited by 95 · see citing works
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“This is accompanied by a reduction in anti-inflammatory (M2) macrophages, which have a high iron releasing capacity [46].”
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 · see citing works
Wlaschek, M., Singh, K., Sindrilaru, A., Crisan, D., & Scharffetter-Kochanek, K. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.036 · Cited by 76 · see citing works
“hypothesized that iron release from M2 macrophages supports proliferation of stromal cells such as fibroblasts as well as of microbiota [127].”
BackgroundThe role of iron homeostasis and iron-mediated ROS in cancer.
Ying, J., Lu, Z.-B., Fu, L., Tong, Y., Wang, Z., Li, W., & Mou, X. (2021) · PubMed Central · Cited by 74 · see citing works
Lech, M., Gröbmayr, R., Weidenbusch, M. J., & Anders, H. (2012) · Mediators of Inflammation · doi:10.1155/2012/951390 · Cited by 73 · see citing works
“In addition, in wounds with vascular lesions and subcutaneous bleeding, erythrocyte-derived iron serves as a DAMP that induces the inflammatory macrophage phenotype, which then again suppresses the wound healing process [45, 46].”
BackgroundFrioni, A., Conte, M. P., Cutone, A., Longhi, C., Musci, G., di Patti, M. C. B., Natalizi, T., Marazzato, M., Lepanto, M. S., Puddu, P., et al. (2014) · BioMetals · doi:10.1007/s10534-014-9740-9 · Cited by 69 · see citing works
Metabolic reprogramming in the immunosuppression of tumor-associated macrophages
Wang, Y., Wang, D., Yang, L., & Zhang, Y. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002426 · Cited by 66 · see citing works
“Hence, M2-polarized macrophages are set in an iron-export mode, while M1-polarized macrophages in an iron-retention mode.([95,96])”
BackgroundIron, lipid peroxidation, and ferroptosis play pathogenic roles in atherosclerosis
Jinson, S., Zhang, Z., Lancaster, G. I., Murphy, A. J., & Morgan, P. K. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae270 · Cited by 69 · see citing works
Nanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications
Meng, T., He, D., Han, Z., Shi, R., Wang, Y., Ren, B., Zhang, C., Mao, Z., Luo, G., & Deng, J. (2024) · Nano-Micro Letters · doi:10.1007/s40820-024-01455-9 · Cited by 63 · see citing works
DeRosa, A., & Leftin, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.614294 · Cited by 55 · see citing works
“This also has an impact on the effects of iron chelators, which have been shown to promote the M1-like macrophage phenotype (73, 74).”
BackgroundIron and Alzheimer’s Disease: From Pathology to Imaging
Tran, D. Q., DiGiacomo, P., Born, D. E., Georgiadis, M., & Zeineh, M. (2022) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2022.838692 · Cited by 57 · see citing works
Molecular regulation of cellular iron balance
Recalcati, S., Gammella, E., Buratti, P., & Cairo, G. (2017) · IUBMB Life · doi:10.1002/iub.1628 · Cited by 55 · see citing works
“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…”
BackgroundSelf-citationIkeda, 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 · see citing works
Punzo, F., Bellini, G., Tortora, C., Pinto, D., Argenziano, M., Pota, E., Paola, A. D., Martino, M. D., & Rossi, F. (2020) · Oncotarget · doi:10.18632/oncotarget.27479 · Cited by 53 · see citing works
“In contrast, M2 macrophages release iron that contributes to cell proliferation [29, 30].”
BackgroundZhang, Z., Hou, L., Song, J.-L., Song, N., Sun, Y., Lin, X., Wang, X.-L., Zhang, F.-Z., & Ge, Y. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.037 · Cited by 52 · see citing works
Qu, Z., Li, P., Zhang, X., & Han, K. (2015) · Journal of Materials Chemistry B · doi:10.1039/c5tb02090e · Cited by 50 · see citing works
Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis
Pirdel, L., & Pirdel, M. (2014) · Reproduction · doi:10.1530/rep-13-0552 · Cited by 49 · see citing works
“Hepcidin-mediated Fpn down-regulation has been reported to result in iron accumulation in M1 macrophages, which may contribute to wound healing or chronic inflammation (Recalcati et al. 2012).”
BackgroundPhysiological implications of NTBI uptake by T lymphocytes
Pinto, J. P., Arezes, J., Dias, V., Oliveira, S. J., Vieira, I. H., Costa, M., Vos, M. R. J., Carlsson, A., Rikers, Y. G. M., Rangel, M., et al. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00024 · Cited by 47 · see citing works
“…interfere with the availability of iron in the extracellular milieu (as proposed in Figure 6) and thus influence the growth rate of adjacent cells, playing a role in normal cell/tumor growth and tissue remodeling, such as already demonstrated for polarized M2 macrophages (Recalcati et al., 2012).”
BackgroundZhang, W., Yao, W., Yan, Q., Ma, F., Shi, X., Zhao, Y., Peng, Y., Wang, J., & Jiang, B. (2013) · Oncology Reports · doi:10.3892/or.2013.2828 · Cited by 45 · see citing works
Excess iron intake induced liver injury: The role of gut-liver axis and therapeutic potential
Liu, Y., Li, G., Lu, F., Guo, Z., Cai, S., & Huo, T. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115728 · Cited by 46 · see citing works
Mice That Are Fed a High-Fat Diet Display Increased Hepcidin Expression in Adipose Tissue
GOTARDO, E. R. M. F., dos Santos, A. N., Miyashiro, R. A., Gambero, S., Rocha, T., Ribeiro, M. L., & Gambero, A. (2013) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.59.454 · Cited by 44 · see citing works
Aerbajinai, W., Ghosh, M. C., Liu, J., Kumkhaek, C., Zhu, J., Chin, K., Rouault, T. A., & Rodgers, G. P. (2019) · Blood Advances · doi:10.1182/bloodadvances.2018026070 · Cited by 44 · see citing works
Prenatal iron exposure and childhood type 1 diabetes
Størdal, K., McArdle, H. J., Hayes, H. E., Tapia, G., Viken, M. K., Lund‐Blix, N. A., Haugen, M. A., Joner, G., Skrivarhaug, T., Mårild, K., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-27391-4 · Cited by 43 · see citing works
The Macrophage Iron Signature in Health and Disease
Mertens, C., Marques, O., Horvat, N. K., Simonetti, M., Muckenthaler, M. U., & Jung, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168457 · Cited by 43 · see citing works
“Moreover, studies have shown that applying NTBI to alternative-like MΦ can initiate a phenotypic switch towards an classical-like phenotype [15,17].”
BackgroundEstablished and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
Petzer, V., Theurl, I., & Weiß, G. (2018) · Pharmaceuticals · doi:10.3390/ph11040135 · Cited by 41 · see citing works
“In contrast, M2 macrophages exert anti-inflammatory effects and these cells are highly specialized for iron recycling from senescent erythrocytes via erythrophagocytosis, yielding approximately 90% of the daily needs of iron for erythropoiesis [30].”
BackgroundInnate Immune Regulation Under Magnetic Fields With Possible Mechanisms and Therapeutic Applications
Lei, H., Pan, Y., Wu, R., & Lv, Y. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.582772 · Cited by 40 · see citing works
Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer
Leftin, A., Ben-Chetrit, N., Klemm, F., Joyce, J. A., & Koutcher, J. A. (2017) · PLOS ONE · doi:10.1371/journal.pone.0184765 · Cited by 36 · see citing works
M2-polarised macrophages in infantile haemangiomas: correlation with promoted angiogenesis
Wang, F., Chen, G., Zhu, J., Zhang, W., Ren, J., Liu, H., Sun, Z., Jia, J., & Zhao, Y. (2013) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2012-201286 · Cited by 39 · see citing works
Zhou, Y., Que, K., Tang, H., Zhang, P., Fu, Q., & Liu, Z. (2020) · Oncology Letters · doi:10.3892/ol.2020.12161 · Cited by 38 · see citing works
“M2 macrophages release iron ions from the labile iron pool, alter the local microenvironment and increase the availability of iron ions in adjacent cells, thereby promoting the proliferation of adja‐ cent cells, increasing collagen deposition and accelerating damage repair and regeneration (5).”
BackgroundThe Potential Role of Ferroptosis in Systemic Lupus Erythematosus
Chen, Q., Wang, J., Xiang, M., Wang, Y., Zhang, Z., Liang, J. F., & Xu, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.855622 · Cited by 38 · see citing works
Iron as a therapeutic target in chronic liver disease
Kouroumalis, E., Tsomidis, I., & Voumvouraki, A. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i4.616 · Cited by 40 · see citing works
The role of iron metabolism in cancer therapy focusing on tumor‐associated macrophages
Dong, D., Zhang, G., Yang, J., Zhao, B., Wang, S., Wang, L., Zhang, G., & Shang, P. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27569 · Cited by 37 · see citing works
“It is now established that, M1 macrophages show high levels of ferritin, low levels of FPN, and changes of hepcidin and TFR1, which favor an iron‐ sequestration mode and are of benefit for inflammatory disorders, while M2 cells express high levels of FPN and low levels of ferritin, which display an iron‐export mode (J…”
BackgroundInfluentialIron Deficiency, Anemia, and the Immune System
Mitterstiller, A., von Raffay, L., & Nairz, M. (2022) · Nutrition and health · doi:10.1007/978-3-031-14521-6_18 · Cited by 35 · see citing works
Leftin, A., Zhao, H., Turkekul, M., de Stanchina, E., Manova, K., & Koutcher, J. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-11899-2 · Cited by 33 · see citing works
Guo, R., Wang, R., Zhang, W., Li, Y., Wang, Y., Wang, H., Li, X., & Song, J. (2025) · Cancer Control · doi:10.1177/10732748251316604 · Cited by 32 · see citing works
“119,120 121-124 In addition, adenosine inhibits TAM function in the tumour microenvironment, affecting its phagocytosis and cytokine production, and the adenosine receptor A2A affects tumour progression by upregulating CXCL5 secretion via the NF-kB pathway.”
Mushenkova, N. V., Nikiforov, N. G., Melnichenko, A. А., Kalmykov, V. A., Shakhpazyan, N. K., Orekhova, V. A., & Orekhov, A. N. (2022) · Biomedicines · doi:10.3390/biomedicines10020452 · Cited by 32 · see citing works
“Due to HO-1-mediated degradation, haem is transformed in biliverdin and subsequently converted into bilirubin, which has anti-inflammatory and anti-oxidant properties [48].”
BackgroundHartmann, S., Tousseyn, T., Döring, C., Flüchter, P., Hackstein, H., Herreman, A., Ponzoni, M., Wolf‐Peeters, C. D., Facchetti, F., Gascoyne, R. D., et al. (2013) · International Journal of Cancer · doi:10.1002/ijc.28273 · Cited by 32 · see citing works
“Ferritin heavy chain upregulation correlates with increased iron retention, described as a bacteriostatic mechanism and usually found in M1-polarized macrophages.(31) Additional genes with proinflammatory properties like CXCL9, STAT1 and HLA-associated transcripts—usually expressed in M1-polarized activated macrophage…”
BackgroundConnor, J. R., Zhang, X., Nixon, A. M., Webb, B., & Perno, J. R. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125272 · Cited by 32 · see citing works
“Moreover, the polarity of the macrophages will be influenced by the iron status of the cells [14, 30].”
BackgroundMaternal iron supplement intake during pregnancy and risk of celiac disease in children
Størdal, K., Haugen, M., Brantsæter, A., Lundin, K., & Stene, L. C. (2013) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2013.09.061 · Cited by 33 · see citing works
Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS
Zhang, W. Z., Oromendia, C., Kikkers, S. A., Butler, J. J., O’Beirne, S. L., Kim, K., O’Neal, W. K., Freeman, C. M., Christenson, S. A., Peters, S. P., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-67047-w · Cited by 31 · see citing works
Xu, J., Xiao, C., Song, W., Cui, X., Pan, M., Wang, Q., Feng, Y., & Xu, Y. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.656626 · Cited by 30 · see citing works
“On one hand, the gene expression of iron regulatory factors would change and iron deposition would exacerbate under inflammatory conditions (Recalcati et al., 2012).”
BackgroundStijlemans, B., Beschin, A., Magez, S., Ginderachter, J. A. V., & BAETSELIER, P. D. (2015) · BioMed Research International · doi:10.1155/2015/819389 · Cited by 30 · see citing works
“In contrast, M2-type MYPS cells (alternatively activated myeloid cells) in trypanotolerant animals (exhibiting reduced anemia/ACD) induced via IL-10 or IL4/IL13 promote induction of anti-inflammatory cytokines like IL10 (crucial for dampening the pathogenic effects of proinflammatory cytokines) and export of iron [139…”
BackgroundFerroptosis: The Potential Target in Heart Failure with Preserved Ejection Fraction
Li, Q., Zhao, Z., Zhou, X., Yan, Y., Shi, L., Chen, J., Fu, B., & Mao, J. (2022) · Cells · doi:10.3390/cells11182842 · Cited by 28 · see citing works
“High intracellular iron activates pro-inflammatory M1 macrophages while reducing anti-inflammatory M2 macrophages [41].”
BackgroundIron Availability in Tissue Microenvironment: The Key Role of Ferroportin
Gammella, E., Correnti, M., Cairo, G., & Recalcati, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062986 · Cited by 28 · see citing works
“In particular, 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 populations [74].”
BackgroundSelf-citationZhong, J., Jiang, R., Liu, N., Cai, Q., Cao, Q., Du, Y., & Zhao, H. (2025) · Antioxidants · doi:10.3390/antiox14070890 · Cited by 29 · see citing works
Guo, S., Jiang, S., Epperla, N., Ma, Y., Maadooliat, M., Ye, Z., Olson, B. F., Wang, M., Kitchner, T., Joyce, J., et al. (2019) · Blood · doi:10.1182/blood-2018-10-879585 · Cited by 26 · see citing works
Iron as an emerging therapeutic target in critically ill patients
Grangé, C., Lux, F., Brichart, T., David, L., Couturier, A., Leaf, D., Allaouchiche, B., & Tillement, O. (2023) · Critical Care · doi:10.1186/s13054-023-04759-1 · Cited by 22 · see citing works
“Furthermore, iron accumulation in M1-polarized macrophages can lead to the persistent proinflammatory state observed in chronic and autoimmune diseases [25].”
BackgroundChang, R., Chu, K., Lin, M., Chu, Y.-H., Hung, Y., & Wei, J. C. (2020) · Current Medical Research and Opinion · doi:10.1080/03007995.2020.1748585 · Cited by 24 · see citing works
Bergström, S. H., Nilsson, M., Adamo, H. H., Thysell, E., Jernberg, E., Stattin, P. E., Widmark, A., Wikström, P., & Bergh, A. R. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157280 · Cited by 24 · see citing works
“Macrophages deliver Fe to cancer cells in other tumor types [45, 46], and accumulation of Fe in prostate cancer cells was found to be associated with poor patient outcome [47].”
BackgroundFerroptosis is an effective strategy for cancer therapy
Khan, A., Huo, Y., Guo, Y., Shi, J., & Hou, Y. (2024) · Medical Oncology · doi:10.1007/s12032-024-02317-5 · Cited by 22 · see citing works
“On the other hand, anti-inflammatory macrophages, or M2 macrophages, are activated by cytokines like IL4, IL10, IL13, CSF1, and TGFβ [94].”
Dias‐Melicio, L. A., Fernandes, R. K., Rodrigues, D. R., Golim, M. D. A., & Soares, Â. M. V. D. C. (2015) · Mediators of Inflammation · doi:10.1155/2015/236839 · Cited by 22 · see citing works
“M1 macrophages are characterized by high microbicidal capacity and secretion of proinflammatory cytokines such as TNF-α, while M2 macrophages present high expression of mannose, galactose, and scavenging receptors, more phagocytic activity, and a phenotype characterized by high expression of IL-10 and low expression o…”
BackgroundFerroptosis: a new target for hepatic ischemia-reperfusion injury?
Guo, S., Li, Z., Liu, Y., Cheng, Y., & Jia, D. (2024) · Free Radical Research · doi:10.1080/10715762.2024.2386075 · Cited by 22 · see citing works
“High intracellular iron levels activate proinflammatory M1 macrophages, accompanied by decreased anti-inflammatory M2 macrophages [114]. in addition, the inflammatory response activated by toll-like receptor 4 (tlR4) is regulated by iron, and tlR4 can promote iron accumulation [115– 117].…”
Kim, H., Hong, J. Y., Jeon, W., Lee, J., Lee, Y. J., & Ha, I. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113776 · Cited by 21 · see citing works
Ferric pyrophosphate citrate: interactions with transferrin
Pratt, R. D., Handelman, G. J., Edwards, T. E., & Gupta, A. (2018) · BioMetals · doi:10.1007/s10534-018-0142-2 · Cited by 21 · see citing works
Selmi, C. F. (2013) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-013-8386-7 · Cited by 20 · see citing works
“including iron absorption and the subsequent polarization of macrophages to theM1 orM2 phenotype [50] whichmay prove”
Wan, D., Zhou, X., Xie, C., Shu, X., Wu, X., & Yin, Y. (2015) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2015.09.013 · Cited by 20 · see citing works
Wang, Z., Li, C., Li, Y., Guo, X., Yan, Z., Fulian, G., & Li, C. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/5414670 · Cited by 19 · see citing works
“, tumor microenvironment which is comprised of various cells, cytokines, and extracellular matrix; among those, tumor-associated macrophages (type II phenotype) are the main source of iron supply [37].”
BackgroundUrinary Metals Concentrations and Biomarkers of Autoimmunity among Navajo and Nicaraguan Men
Scammell, M. K., Sennett, C. M., Laws, R. L., Rubin, R. L., Brooks, D. R., Amador, J. J., López-Pilarte, D., Ramírez‐Rubio, O., Friedman, D. J., McClean, M. D., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17155263 · Cited by 19 · see citing works
“Molecular mechanisms are likely metal-induced generation of reactive oxygen species [24], followed by oxidative damage to tissues, organs and the genetic material [25].”
BackgroundReprogramming 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 19 · see citing works
dECM restores macrophage immune homeostasis and alleviates iron overload to promote DTPI healing
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- Authors
- Recalcati, S., Locati, M., Gammella, E., Invernizzi, P., & Cairo, G.
- Affiliations
- University of Milan (IT)
- IRCCS Humanitas Research Hospital (IT)
- Corresponding author
- Recalcati, Stefania
- Venue
- Autoimmunity Reviews
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 11
- Issue
- 12
- Pages
- 883-889
- ISSN
- 1568-9972 (ISSN-L)
- OpenAlex
- W1967017135
- Cited by
- 150
- References
- 80
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 13 · 2023: 6 · 2022: 15 · 2021: 9 · 2020: 12 · 2019: 6 · 2018: 13 · 2017: 8 · 2016: 6 · 2015: 11 · 2014: 14 · 2013: 12 · 2012: 3
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Autoimmunity Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- macrophage polarization, M1 macrophages, M2 macrophages, autoimmunity, chronic inflammation, anemia of chronic disease, iron accumulation, iron release, tumor growth, tissue remodeling, macrophage heterogeneity
- MeSH terms
- Animals, Cell Differentiation, Cell Transformation, Neoplastic, Humans, Iron, Macrophage Activation, Macrophages, Autoimmunity, Inflammation Mediators, Cell Proliferation, Immunomodulation
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