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Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway
Abstract
The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway.
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“Of note, IrpLyzCre(+) mice display a marked increase in plasma ferritin concentration (Figure 1E), as predicted for animals with augmented macrophage ferritin expression (Cohen et al., 2010).”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Cohen et al., 2010
In the citing paper
“This result supports earlier work concluding that macrophages represent a major source of ferritin in the blood (Cohen et al., 2010).”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Cohen et al., 2010
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Nairz, M., Ferring-Appel, D., Casarrubea, D., Sonnweber, T., Viatte, L., Schroll, A., Haschka, D., Fang, F. C., Hentze, M. W., Weiss, G., et al. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.06.017 · Cited by 103
Cellular and mitochondrial iron homeostasis in vertebrates
Chen, C., & Paw, B. H. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.01.003 · Cited by 111
Ferritin Light Chain Confers Protection Against Sepsis-Induced Inflammation and Organ Injury
Zarjou, A., Black, L. M., McCullough, K., Hull, T. D., Esman, S. K., Boddu, R., Varambally, S., Chandrashekar, D. S., Feng, W., Arosio, P., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00131 · Cited by 109
“Since the major source of circulating ferritin is FtL (16), we postulated that this elevated serum ferritin may play a role in inflammation during sepsis.”
BackgroundInfluentialInflammation associated anemia and ferritin as disease markers in SLE
Vanarsa, K., Ye, Y., Han, J., Xie, C., Mohan, C., & Wu, T. (2012) · Arthritis Research & Therapy · doi:10.1186/ar4012 · Cited by 101
“In mouse models, the macrophage is the main source of serum ferritin [27].”
BackgroundMacrophages: central regulators of iron balance
Gammella, E., Buratti, P., Cairo, G., & Recalcati, S. (2014) · Metallomics · doi:10.1039/c4mt00104d · Cited by 100
Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity
Thévenod, F., & Wolff, N. A. (2015) · Metallomics · doi:10.1039/c5mt00215j · Cited by 101
Ruscitti, P., Berardicurti, O., Benedetto, P. D., Cipriani, P., Iagnocco, A., Shoenfeld, Y., & Giacomelli, R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01130 · Cited by 100
“In addition, FeH+/IL-12+ macrophages have been shown in the infiltrate of AOSD and secondary HLH (15, 18), which may further release FeH, following inflammatory stimuli (19), and thus contributing to the inflammatory loop (20).”
BackgroundTraglia, M., Girelli, D., Biino, G., Campostrini, N., Corbella, M., Sala, C., Masciullo, C., Viganò, F., Buetti, I., Pistis, G., et al. (2011) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2011-100061 · Cited by 97
“C282Y increases transferrin saturation and cell iron uptake. However, the concomitant hepcidin downregulation favours iron release from macrophages. On one side this translates into the vicious cycle of further enhancing transferrin saturation, but on the other side, if the secreted ferritin is related to macrophage i…”
BackgroundIron metabolism: current facts and future decisions
Tandara, L., & Salamunić, I. (2012) · Biochemia Medica · doi:10.11613/bm.2012.034 · Cited by 102
Iron Uptake Mediated by Binding of H-Ferritin to the TIM-2 Receptor in Mouse Cells
Han, J., Seaman, W. E., Di, X., Wang, W., Willingham, M. C., Torti, F. M., & Torti, S. V. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023800 · Cited by 93
“For example, the macrophage, which can serve as a source of circulating ferritin [53] may also secrete ferritin locally [16,55], and this may serve as a paracrine source of ferritin for uptake by TIM-2.”
BackgroundHepatic iron is the major determinant of serum ferritin in NAFLD patients
Ryan, J. D., Armitage, A. E., Cobbold, J., Banerjee, R., Borsani, O., Dongiovanni, P., Neubauer, S., Morovat, R., Wang, L. M., Pasricha, S., et al. (2017) · Liver International · doi:10.1111/liv.13513 · Cited by 93
Endoplasmic reticulum anchored heme-oxygenase 1 faces the cytosol
Gottlieb, Y., Truman-Rosentsvit, M., Cohen, L. A., Leichtmann‐Bardoogo, Y., & Meyron‐Holtz, E. G. (2012) · Haematologica · doi:10.3324/haematol.2012.063651 · Cited by 88
“postnuclear fraction, lysates originating from equal amounts of cells were separated by 14% SDS-PAGE as described.(13) Anti-GFP”
MethodIron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities
Paterek, A., Mackiewicz, U., & Ma̧czewski, M. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28820 · Cited by 88
“Nevertheless, studies in a mouse model showed that serum ferritin was composed of mainly L‐ferritin, with low iron content, suggesting that most of the serum ferritin is apoferritin (Cohen et al., 2010).”
BackgroundRuscitti, P., Cipriani, P., Ciccia, F., Masedu, F., Liakouli, V., Carubbi, F., Berardicurti, O., Guggino, G., Benedetto, P. D., Bartolomeo, S. D., et al. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2016.09.016 · Cited by 85
“[29] Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, Sougrat R, Morgenstern A, Galy B, Hentze MW, Lazaro FJ, Rouault TA, Meyron-Holtz EG.”
BackgroundsCD163 in AOSD: a biomarker for macrophage activation related to hyperferritinemia
Colafrancesco, S., Priori, R., Alessandri, C., Astorri, E., Perricone, C., Blank, M., Agmon‐Levin, N., Shoenfeld, Y., & Valesini, G. (2014) · Immunologic Research · doi:10.1007/s12026-014-8563-7 · Cited by 83
“[11] demonstrated ferritin production from macrophages through a non-classical secretory pathway in a mouse model.”
BackgroundBoyce, M. J., Warrington, S., Cortezi, B., Zöllner, S. K., Vauléon, S., Swinkels, D. W., Summo, L., Schwoebel, F., & Riecke, K. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13433 · Cited by 83
“Under conditions of elevated iron stores in the reticuloendothelial system (RES), the inhibition of hepcidin should release intracellular iron from the RES and thus, over time, should decrease serum ferritin concentrations (Cohen et al., 2010), as observed in a study in cancer patients with ACD and high baseline ferri…”
Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications
Kontoghiorghes, G. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612928 · Cited by 91
A possible role for secreted ferritin in tissue iron distribution
Meyron‐Holtz, E. G., Moshe-Belizowski, S., & Cohen, L. A. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0582-0 · Cited by 78
“Also human monocyte- or murine bone marrow-derived macrophages secrete ferritin actively to the culture medium (Leimberg et al. 2008; Cohen et al. 2010).”
BackgroundMethodInfluentialGowda, P., Patrick, S., Joshi, S. D., Kumawat, R. K., & Sen, E. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155496 · Cited by 79
Leichtmann‐Bardoogo, Y., Cohen, L. A., Weiss, A., Marohn, B., Schubert, S., Meinhardt, A., & Meyron‐Holtz, E. G. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00007.2012 · Cited by 77
“Macrophages secrete ferritin that is taken up by human erythroid precursors (24) and are likely a source for serum ferritin through a nonclassical secretion pathway (6).”
Time-course assessment of the aggregation and metabolization of magnetic nanoparticles
Rojas, J. M., Gavilán, H., del Dedo, V., Lorente-Sorolla, E., Sanz-Ortega, L., da Silva, G. B., Costo, R., Pérez-Yagüe, S., Talelli, M., Marciello, M., et al. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.05.047 · Cited by 76
Macrophages and Iron: A Special Relationship
Recalcati, S., & Cairo, G. (2021) · Biomedicines · doi:10.3390/biomedicines9111585 · Cited by 81
“In fact, splenectomy strongly reduced the increase in circulating ferritin observed in mice with IRP2-targeted deletion [43].”
BackgroundLaskar, A., Ghosh, M., Khattak, S. I., Li, W., & Yuan, X. (2012) · Nanomedicine · doi:10.2217/nnm.11.148 · Cited by 75
Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer
Orlandi, R., De Bortoli, M., Ciniselli, C. M., Vaghi, E., Caccia, D., Garrisi, V., Pizzamiglio, S., Veneroni, S., Bonini, C., Agresti, R., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdt490 · Cited by 74
Metadata
- Authors
- Cohen, L. A., Gutierrez, L., Weiss, A., Leichtmann-Bardoogo, Y., Zhang, D.-L., Crooks, D. R., Sougrat, R., Morgenstern, A., Galy, B., Hentze, M. W., Lazaro, F. J., Rouault, T. A., & Meyron-Holtz, E. G.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Departamento de Ciencia y Tecnología de Materiales y Fluidos, Universidad de Zaragoza, Zaragoza, Spain;
- Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel;
- Molecular Medicine Program and
- National Institutes of Health (US)
- European Molecular Biology Laboratory (DE)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-09-02
- Volume
- 116
- Issue
- 9
- Pages
- 1574-1584
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2153170511
- Cited by
- 452
- References
- 53
- Citations by year
- 2026: 8 · 2025: 34 · 2024: 33 · 2023: 30 · 2022: 43 · 2021: 45 · 2020: 35 · 2019: 34 · 2018: 31 · 2017: 24 · 2016: 23 · 2015: 33 · 2014: 18 · 2013: 24 · 2012: 17
- FWCI
- 11.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- serum ferritin, macrophages, lysosomal secretion, L subunit, H subunit, C-terminal truncation, glycosylation, proximal tubular epithelial cells, splenic macrophages, iron stores, mice
- MeSH terms
- Amino Acid Sequence, Animals, Enzyme-Linked Immunosorbent Assay, Ferritins, Glycosylation, Iron, Lysosomes, Macrophages, Male, Mice, Inbred C57BL, Molecular Sequence Data, Sequence Homology, Amino Acid, Iron Overload, Protein Subunits, Mice, Secretory Pathway
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