Cited by 452Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

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Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Cohen, Lyora A., Gutierrez, Lucia, Weiss, Avital, Leichtmann-Bardoogo, Yael, Zhang, De-liang, Crooks, Daniel R., Sougrat, Rachid, Morgenstern, Avigail, Galy, Bruno, Hentze, Matthias W., Lazaro, Francisco J., Rouault, Tracey A., Meyron-Holtz, Esther G.·2010·Blood

DOI 10.1182/blood-2009-11-253815

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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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“Mechanisms of ferritin glycosylation and secretion are controversial, some Authors suggesting a N-glycosylation pattern implying secretion through the ER-Golgi pathway,(6,19) while other supporting an accumulation of glucose similar to the glycation of hemoglobin in RBCs and a lysosomal pathway of ferritin secretion.(…”
Background
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“It has, however, become increasingly evident that several clinical conditions can be associated with elevated serum ferritin levels in the absence of iron overload [28, 31], while the identity of serum ferritin is not clear and its source is still a matter of debate [32].”
Background
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Background
Iron kinetics and laboratory assessment
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Result
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“We assume that it could be associated with macrophages (Figures 6 and 7, c and d), as macrophages have recently been recognised as a new source of serum ferritin (25, 28).”
Background
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“Macrophages are the main source of serum ferritin [6].”
Background
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“It can also be secreted by different cell types including hepatocytes, Kupffer cells, and the reticuloendothelial system [36,38,39].”
Background
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“used a murine model to clarify cellular sources of serum ferritin and concluded that (i) serum ferritin contains less iron than does liver ferritin and (ii) macrophages and kidney proximal tubule cells are likely the major sources of serum ferritin [2].”
Method
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“In inﬂammatory states, secretion of ferritin from hepatocytes and macrophages (Cohen et al, 2010) leads to hyperferritinemia.”
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Background
Cellular Iron Homeostasis
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Background
Iron metabolism
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“Легколанцюговий феритин краще накопичує залізо і переважає в клітинах селезінки та печінки, тоді як важколанцюговий феритин переважає в серці та нирках [8].”
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“It is important to remember that ferritin in inflammatory reactions can be actively secreted by hepatocytes [19] and macrophages [20].”
Background
Structural and functional relationship of mammalian and nematode ferritins
Lewandowski, J., Komur, A. A., & Sobańska, D. (2021) · Biotechnologia · doi:10.5114/bta.2021.111110 · Cited by 2
“The abundant serum ferritin normally present in circulation was found to be initially secreted by macrophages in vivo (Cohen et al., 2010).”
Background
The clinical applications of ferritin
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“Chelation therapy is the favored choice for treatment of iron overload, for example using deferoxamine as iron chelator and administered either intravenously or subcutaneously (35).”
Background
Serum untargeted metabolomics alterations in systemic lupus erythematosus patients with elevated serum ferritin
Li, N., Chai, R., Xu, X., Xu, Q., Liang, J., Wang, D., Zhang, H., Feng, X., Geng, L., & Sun, L. (2025) · Scientific Reports · doi:10.1038/s41598-025-06170-y · Cited by 2
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Temporal and spatial resolution of magnetosome degradation at the subcellular level in a 3D lung carcinoma model
Gubieda, A. G., Gandarias, L., Pósfai, M., Pattammattel, A., Fdez-Gubieda, M. L., Abad, A., & Garcı́a-Prieto, A. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02788-8 · Cited by 2
“…can transport free Fe 2 + and is the sole known iron exporter in vertebrates [41]; or as the ferrihydrite within ferritin, as the ferritin located within lysosomes has previously been reported to be secreted through a non-classical lysosomal secretion pathway or via secretory autophagy [42, 43].”
Background
Iron biomarkers predict peripheral artery disease in females
Agarvas, A. R., Kopf, S., Lopes, T. J. S., Atkins, J. L., Thalmann, P., Fernández‐Real, J. M., Nawroth, P. P., & Muckenthaler, M. U. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.119111 · Cited by 2
The ability of CD4dimCD8+ T cells to distinguish between Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis and pediatric infectious mononucleosis
Liu, C., Zou, A., Wang, X., & Huang, C. (2025) · Immunologic Research · doi:10.1007/s12026-025-09597-7 · Cited by 2
HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease
Kouroumalis, E., Tsomidis, I., & Voumvouraki, A. (2025) · Biomedicines · doi:10.3390/biomedicines13030683 · Cited by 2
Hyperferritinemia and COVID-19?
Čepelak, I., Dodig, S., & Vučenik, I. (2020) · Rad Hrvatske akademije znanosti i umjetnosti Medicinske znanosti · doi:10.21857/ygjwrcdv0y · Cited by 2
Effects of Andrographis paniculata Leaf Extract on C-Reactive Protein and Serum Ferritin in Lipopolysaccharide-Induced Sepsis Model Rat
Salsabela, R., Widyastiti, N. S., Retnoningrum, D., Ariosta, A., & Susilaningsih, N. (2023) · Jurnal Kedokteran Diponegoro (Diponegoro Medical Journal) · doi:10.14710/dmj.v12i3.37645 · Cited by 2
Iron Homeostasis and Inflammatory Status in Mice Deficient for the Cystic Fibrosis Transmembrane Regulator
Deschemin, J., Allouche, S., Brouillard, F., & Vaulont, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0145685 · Cited by 2
Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis
Schneider, R., Canny, S., & Mellins, E. (2019) · Springer eBooks · doi:10.1007/978-3-030-22094-5_21 · Cited by 2
Sex-dependent deterioration of cardiac function and molecular alterations in age- and disease-associated RAGE overexpression
Winterhalter, P. R., Wirkner, M., Bartling, B., Wächter, K., Уразова, А. Н., Großkopf, A., Diez, C., Szabo, G. B., & Simm, A. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111635 · Cited by 2
Assessment of some Physiological Biomarkers in COVID-19 Patients in Thi-Qar, Iraq.
Jouda, J., Jabbar, E. A. K., Abdulhadi, F. S., & Kamil, Y. A. (2022) · PubMed Central · doi:10.22092/ari.2022.357267.2006 · Cited by 2
Ferritin and hiperferritinemic syndrome: Its impact on the seriously ill; current concepts
Esper, R. C., Pérez, C. P., Mendoza, A. D. Z., Márquez, J. M. M., Maldonado, R. N., Meza-Ayala, C. M., Córdova, D. M. C., & Córdova, C. A. C. (2015) · Medicina Crítica · Cited by 2
Laboratory Features and Pathology of the Cytokine Storm Syndromes
Rosado, F., & Gopal, P. (2019) · Springer eBooks · doi:10.1007/978-3-030-22094-5_4 · Cited by 2
SARS-CoV-2 and Covid-19 ImmunopathogenesisPreprint
Boechat, A. L., Pessoa, B., Soares, C. A. S., Barroso, C. T., Vila, D. J. C., Barbosa, E. M. L., Seffair, I. D. A., de Melo, J. V. O., Becil, J. N., Rebouças, M. P., et al. (2020) · Preprints.org · doi:10.20944/preprints202008.0020.v1 · Cited by 2
Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis and iron homeostasisPreprint
Giroud‐Gerbetant, J., Sotillo, F., Hernández, G., Lynch, C. J., Ruano, I., Siri, B., Sebastián, D., Antonio Zorzano, A., Artuch, R., Ormazábal, A., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.15.456393 · Cited by 2
Ferritin Levels on Hospital Admission Predict Hypoxic-Ischemic Encephalopathy in Patients After Out-of-Hospital Cardiac Arrest: A Prospective Observational Single-Center Study
Nickelsen, S., Darrelmann, E. G., Seidlmayer, L. K., Fink, K., Britsch, S., Duerschmied, D., Scharf, R. E., Elsaesser, A., & Helbing, T. (2024) · Journal of Intensive Care Medicine · doi:10.1177/08850666241252602 · Cited by 1
“18 The cellular source and the mechanism of serum ferritin regulation observed in patients after OHCA remains unclear.”
Serum ferritin as a predictive biomarker for PEG IFNα-2b efficacy in chronic hepatitis B treatment
Chen, M., Wang, C., Lin, M., & Cai, S. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1603286 · Cited by 1
Hyperferritinemia Is Associated with Higher Adiposity, Metabolic Syndrome, and Hepatic Dysfunction, Mainly Affecting Men: A Study in Southern Brazil
Zanuzo, K., Nishiyama, M. F., Koehnlein, E. A., & Grassiolli, S. (2025) · Pathophysiology · doi:10.3390/pathophysiology32040064 · Cited by 1
“The exact origin of circulating SF is not fully understood, although macrophages are considered the primary source of systemic ferritin [9,10].”
Species-Specific Isotope Dilution Methodology for the SI Traceable Quantification of Serum Human Ferritin Light Chain (FTL)
Ward-Deitrich, C. L., Nehete, S. V., Busto, M. E. D. C., Hill, S., Robertson, F. P., Luckau, L., Hannemann, H., Fox, B. J., & Infante, H. G. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.5c04597 · Cited by 1
Pretreatment hyperferritinaemia as an independent prognostic marker in metastatic solid tumors treated with immune checkpoint inhibitors
Açar, F. P., Acar, C., Yüksel, H. Ç., Şahin, G., & Karaca, B. (2025) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2025.2602806 · Cited by 1
“While the SF level rises in the context of systemic inflammation, it originates largely from reticuloendothelial cells – particularly macrophages – via a non-classical secretory pathway rather than from hepatocytes [25].”
Quando la linfoistiocitosi emofagocitica è secondaria
Ventresca, S., Fabbri, E., Bracaglia, C., Gasperini, P., Filippini, B., Libertucci, F., Bigucci, B., Pericoli, R., & Vergine, G. (2022) · Medico e Bambino · doi:10.53126/meb41097 · Cited by 1
Relação entre os níveis de ferritina e o prognóstico da COVID-19
Júnior, E. C. S. D. S., Medeiros, A. P. D. F., Silva, I. V. E., & Silva, R. D. F. E. (2022) · Revista de Medicina · doi:10.11606/issn.1679-9836.v101i1e-190974 · Cited by 1
Hemochromatosis Mimicked Gaucher Disease: Role of Hyperferritinemia in Evaluation of a Clinical Case
Zizzo, C., Ruggeri, I., Colomba, P., Argano, C., Francofonte, D., Zora, M., Marsana, E. M., Duro, G., & Corrao, S. (2022) · Biology · doi:10.3390/biology11060914 · Cited by 1
“Hyperferritinemia is thought to be a consequence of the storage of iron in Gaucher cells; recent studies suggest that macrophages are directly involved in serum ferritin production [24], and some newly diagnosed patients with GD present with massive infiltration of iron-stained Gaucher cells in the bone marrow [25].”
Background
Assessment of Hemophagocytic Lympho‐Histiocytosis ( HLH ) in the Setting of Adult Acute Liver Failure
Anouti, A., Dahshi, H., Rule, J. A., Wysocki, C., Lee, W. M., & Tujios, S. R. (2025) · Journal of Viral Hepatitis · doi:10.1111/jvh.70050 · Cited by 1
Complicated Hepatitis A Virus Infection: A Report of Three Cases from Single Tertiary Referral Center
Alhaddad, O., Elsabaawy, M. M., Gameel, K. A., Elfauomy, M., Hendy, O., & Rewisha, E. A. (2016) · Journal of Clinical Intensive Care and Medicine · doi:10.29328/journal.jcicm.1001003 · Cited by 1
“Interestingly, ferritin is primarily produced by splenic macrophages through a nonclassical secretory pathway and a very high ferritin level strongly suggests macrophage activation and diagnosis of MAS [14].”
BackgroundInfluential
Use of oral iron in managing iron deficiency anemia in children with intestinal failure
Alsaleem, B., Al-Banyan, N., Alamer, A., Asdaq, S. M. B., Mohzari, Y. A., Alrahili, M. M., Albasheer, A. B., Alrashed, A. A., Alamri, A. S., Alsanie, W. F., et al. (2021) · Journal of King Saud University - Science · doi:10.1016/j.jksus.2021.101601 · Cited by 1
Clinical and pathogenetic significance of the determination of serum ferritin in coronavirus disease (COVID-19)
Zhilenkova, Y. I., & Chernysh, N. Y. (2021) · Laboratory Service · doi:10.17116/labs20211004141 · Cited by 1
Iron-Deficiency Anemia of Gastrointestinal Origin
Dharmarajan, T. S., Lourdusamy, D., & Pitchumoni, C. S. (2021) · Springer eBooks · doi:10.1007/978-3-030-30192-7_24 · Cited by 1
Anemia Risk in Relation to Occupational and Environmental Lead Exposure among Inhabitants of Enyigba Lead-Zinc Mining Community in Ebonyi State, Nigeria
Otuu, F. C. (2022) · Advances in Clinical Toxicology · doi:10.23880/act-16000245 · Cited by 1
Zinc Protoporphyrin to Heme Ratio versus Ferritin as a Measure of Iron Sufficiency in Preterm Infants
Mostafa, M., Almonaem, E. R. A., El-Shimi, O. S., & Elmalky, Y. S. (2023) · Benha Medical Journal · doi:10.21608/bmfj.2023.200539.1783 · Cited by 1
Laboratory Features and Pathology of Cytokine Storm Syndromes
Rosado, F., & Gopal, P. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-59815-9_5 · Cited by 1
Iron and Heme Transport and Trafficking
Yien, Y. Y., & Paw, B. H. (2004) · Wiley eBooks · doi:10.1002/9781119951438.eibc2117 · Cited by 1
Effectiveness of zinc fortified drinking water on zinc intake, status and morbidity of rural Kenyan pre-school children
Chopera, P. (2016) · doi:10.18174/375834 · Cited by 1
Antiferromagnetic switch in serumPreprint
Raja, S. O., Chatterjee, S., & Dasgupta, A. K. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/211102 · Cited by 1
The Spectrum of Hyperferritinemic SyndromesPreprint
Stoian, M., & Scarlat, G. (2023) · Preprints.org · doi:10.20944/preprints202306.0690.v1
Intravenous iron therapy with ferric carboxymaltose results in a rapid and sustained rise in myocardial iron content through a non-canonical pathway: a translational studyPreprint
Vera‐Aviles, M., Kabir, S., Shah, A., Polzella, P., Lim, Y., Buckley, P., Ball, C., Swinkels, D. W., Matlung, H. L., Blans, C., et al. (2024) · medRxiv · doi:10.1101/2024.01.18.24301496 · Cited by 1
“Because plasma ferritin derives primarily from macrophages, uptake of iron-carbohydrate complexes by reticuloendothelial macrophages is closely followed by a rise in plasma ferritin 22-23 .”
Background
IRON HOMEOSTASIS IN IMMUNE MONONUCLEAR CELLS: A POTENTIAL ROLE IN ATHEROGENESIS
Marques, L. (2015) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · doi:10.13140/rg.2.2.24210.40643
Retinoids and Bone
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NASA Sponsors Symposium on Remote Sensing and Control of Insect-Transmitted Diseases
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Analysis of single nucleotide polymorphisms with opposite effects on serum iron parameters in South African patients with multiple sclerosis
Moremi, K. E. (2014) · SUNScholar (Stellenbosch University)
The regulation of human iron metabolism in hypoxia
Govus, A. D. (2015) · Australasian Journal of Paramedicine
Ferritin Upregulates Hepatic Expression of
Feng, Q., Migas, M. C., Waheed, A., Britton, R. S., & Robert, E. (2012)

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: Zhang, De-liang
Crooks, Daniel R.
Sougrat, Rachid
Galy, Bruno
Hentze, Matthias W.
Rouault, Tracey A.
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
DOI: 10.1182/blood-2009-11-253815
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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Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

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