Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo
Open accessAbstract
Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells. We hypothesized that macrophage Nramp1 may participate in the recycling of iron acquired from phagocytosed senescent erythrocytes. To evaluate the role of Nramp1 in vivo, the iron parameters of WT and KO mice were analyzed after acute and chronic induction of hemolytic anemia. We found that untreated KO mice exhibited greater serum transferrin saturation and splenic iron content with higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression. Furthermore, hepatocyte iron content and hepcidin mRNA levels were dramatically lower in KO mice, indicating that hepcidin levels can be regulated by low-hepatocyte iron stores despite increased transferrin saturation. After acute treatment with the hemolytic agent phenylhydrazine (Phz), KO mice experienced a significant decrease in transferrin saturation and hematocrit, whereas WT mice were relatively unaffected. After a month-long Phz regimen, KO mice retained markedly increased quantities of iron within the liver and spleen and exhibited more pronounced splenomegaly and reticulocytosis than WT mice. After injection of 59 Fe-labeled heat-damaged reticulocytes, KO animals accumulated erythrophagocytosed 59 Fe within their liver and spleen, whereas WT animals efficiently recycled phagocytosed 59 Fe to the marrow and erythrocytes. These data imply that without Nramp1, iron accumulates within the liver and spleen during erythrophagocytosis and hemolytic anemia, supporting our hypothesis that Nramp1 promotes efficient hemoglobin iron recycling in macrophages. Our observations suggest that mutations in Nramp1 could result in a novel form of human hereditary iron overload.
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Iron is transported across the phagolysosomal membrane by DMT1 and NRAMP1, whereas FPN1 mediates iron export to the circulation, where iron is incorporated in TF for cargo to tissues and organs.
“Iron can then be transported across the phagolysosomal membrane by DMT1 and NRAMP1, whereas FPN1 mediates iron export to the circulation (Abboud and Haile, 2000;Soe-Lin et al., 2009), where iron is incorporated in TF for cargo to tissues and organs.”
From Iron in infection and immunity (2020) · cites this paper as Soe-Lin et al., 2009
The paper describes Nramp1 in phagolysosomal membranes and, in the Discussion, says it makes iron available for export by ferroportin. Its introductory passage says exported iron binds transferrin and travels to bone marrow. It discusses DMT1 expression in the duodenum, but does not establish that DMT1 transports iron across the phagolysosomal membrane. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNRAMP1 likely transports iron from phagosomes and other microorganism-containing vacuoles to macrophage cytoplasm, thereby starving vacuolar microorganisms of iron.
“most studies suggest that NRAMP1 transports iron from phagosomes and other vacuoles that contain microorganisms to the cytoplasm of macrophages76–78, thereby starving vacuolar microorganisms of iron.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [76]
In steady-state conditions, RBC recycling mainly takes place in the spleen.
“In steady-state conditions, RBC recycling mainly takes place in the spleen [48, 213].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [213]
This pathway is important for iron recycling after erythrophagocytosis and serves as a mechanism of nutrient withdrawal efficient in host defense against Mycobacterium, Salmonella, and Leishmania species.
“This pathway is important for iron recycling after erythrophagocytosis [213] and serves as a mechanism of nutrient withdrawal that is particularly efficient in host defense against Mycobacterium, Salmonella, and Leishmania species [31].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [213]
Nramp1 lowers phagosomal iron and restricts vacuolar growth of Salmonella Typhimurium, Leishmania donovani, and Mycobacterium bovis, but not cytosolic Listeria monocytogenes.
“Nramp1 reduces Fe concentration in phagosomes, restricting the vacuolar growth of intracellular pathogens such as Salmonella enterica serovar Typhimurium (Salmonella), Leishmania donovani and Mycobacteriun bovis, but not Listeria monocytogenes that exhibit a cytosolic life style (56–60).”
From Innate Nutritional Immunity (2018) · cites this paper as [58]
Macrophages without Nramp1 activity have higher intracellular iron, which is linked to greater pathogen load in endosomes.
“Macrophages lacking Nramp1 activity exhibit higher intracellular Fe content, which is associated with increased pathogen load in endosomes (57, 58).”
From Innate Nutritional Immunity (2018) · cites this paper as [58]
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Cites
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., & Kaplan, J. (2004) · Science · doi:10.1126/science.1104742 · Cited by 4,803 · see citing works
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., & Ganz, T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420945 · Cited by 2,650 · see citing works
Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., & Loréal, O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008923200 · Cited by 1,697 · see citing works
Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter
Donovan, A., Brownlie, A., Zhou, Y., Shepard, J., Pratt, S. J., Moynihan, J., Paw, B. H., Drejer, A., Barut, B., Zapata, A., et al. (2000) · Nature · doi:10.1038/35001596 · Cited by 1,667 · see citing works
McKie, A. T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., Miret, S., Bomford, A., Peters, T. J., Farzaneh, F., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80425-6 · Cited by 1,422 · see citing works
The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis
Donovan, A., Lima, C. A., Pinkus, J. L., Pinkus, G. S., Zon, L. I., Robine, S., & Andrews, N. C. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.01.003 · Cited by 1,275 · see citing works
A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism
Abboud, S., & Haile, D. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000713200 · Cited by 1,267 · see citing works
Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene
Fleming, M. D., Trenor, C. C., Su, M. A., Foernzler, D., Beier, D. R., Dietrich, W. F., & Andrews, N. C. (1997) · Nature Genetics · doi:10.1038/ng0897-383 · Cited by 1,159 · see citing works
Vidal, S., Tremblay, M. L., Govoni, G., Gauthier, S., Sebastiani, G., Malo, D., Skamene, E., Olivier, M., Jothy, S., & Gros, P. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.3.655 · Cited by 603 · see citing works
Suppression of hepcidin during anemia requires erythropoietic activity
Pak, M., Lopez, M. A., Gabayan, V., Ganz, T., & Rivera, S. (2006) · Blood · doi:10.1182/blood-2006-06-028787 · Cited by 472 · see citing works
Eaton, J. W., & Qian, M. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00772-4 · Cited by 389 · cited 1× · see citing works
“Any disturbances in this normally efficient and tightly regulated process can result in anemia of chronic disease (6–9), iron overload (10), or other pathologies (11, 12).”
BackgroundMolecular control of iron transport
Ganz, T. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070802 · Cited by 353 · cited 2× · see citing works
“Importantly, the amount of iron in macrophages available for erythropoiesis is limited by increased hepcidin levels (17, 26).”
BackgroundForbes, J. R., & Gros, P. (2003) · Blood · doi:10.1182/blood-2003-02-0425 · Cited by 288 · see citing works
Autocrine formation of hepcidin induces iron retention in human monocytes
Theurl, I., Theurl, M., Seifert, M., Mair, S., Nairz, M., Rumpold, H., Zoller, H., Bellmann-Weiler, R., Niederegger, H., Talasz, H., et al. (2008) · Blood · doi:10.1182/blood-2007-05-090019 · Cited by 275 · see citing works
Lin, L., Valore, E. V., Nemeth, E., Goodnough, J. B., Gabayan, V., & Ganz, T. (2007) · Blood · doi:10.1182/blood-2007-04-087593 · Cited by 267 · see citing works
Canonne-Hergaux, F., Zhang, A.-S., Ponka, P., & Gros, P. (2001) · Blood · doi:10.1182/blood.v98.13.3823 · Cited by 169 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Bothwell TH, Charlton RW, Cook JD, Finch CA (1979) Iron Metabolism in Man (Black- well Scientific, Oxford, UK).
Cited by
Sorted by citations
Two to tango: Regulation of Mammalian iron metabolism
Hentze, M. W., Muckenthaler, M. U., Galy, B., & Camaschella, C. (2010) · Cell · doi:10.1016/j.cell.2010.06.028 · Cited by 2,120 · see citing works
Ganz, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00008.2013 · Cited by 1,122 · see citing works
Regulation of cellular iron metabolism
Wang, J., & Pantopoulos, K. (2011) · Biochemical Journal · doi:10.1042/bj20101825 · Cited by 986 · see citing works
Iron homeostasis in host defence and inflammation
Ganz, T., & Nemeth, E. (2015) · Nature Reviews Immunology · doi:10.1038/nri3863 · Cited by 843 · see citing works
Iron in infection and immunity
Nairz, M., & Weiss, G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100864 · Cited by 359 · see citing works
Iron at the interface of immunity and infection
Nairz, M., Haschka, D., Demetz, E., & Weiss, G. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00152 · Cited by 325 · see citing works
“…immune cells by a process called erythrophagocytosis before being degraded leading to recovery of heme which is further processed by the enzyme heme oxygenase-1 (HO-1) yielding equal amounts of iron, biliverdin and carbon-monoxid (Delaby et al., 2005; Knutson et al., 2005; Soe-Lin et al., 2009).”
BackgroundAn overview of molecular basis of iron metabolism regulation and the associated pathologies
Silva, B., & Faustino, P. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.03.011 · Cited by 300 · see citing works
Macrophages and Systemic Iron Homeostasis
Ganz, T. (2012) · Journal of Innate Immunity · doi:10.1159/000336423 · Cited by 281 · see citing works
Iron metabolism and the innate immune response to infection
Johnson, E. E., & Wessling-Resnick, M. (2012) · Microbes and Infection · doi:10.1016/j.micinf.2011.10.001 · Cited by 253 · see citing works
“Nramp1 is a pH-dependent divalent metal transporter that localizes to phagosomal compartments and reduces intraphagosomal iron [45] and macrophage recycling of erythrophagocytosed iron is defective in Nramp1 knockout mice [46].”
BackgroundOxidative Stress and the Homeodynamics of Iron Metabolism
Bresgen, N., & Eckl, P. (2015) · Biomolecules · doi:10.3390/biom5020808 · Cited by 247 · see citing works
Sanchez, K. K., Chen, G. Y., Schieber, A. M. P., Redford, S. E., Shokhirev, M. N., Leblanc, M., Lee, Y. M., & Ayres, J. S. (2018) · Cell · doi:10.1016/j.cell.2018.07.016 · Cited by 175 · see citing works
“…studies has been C57BL/6 mice, which has a non-functional allele of Nramp1, a divalent metal (iron and manganese) transporter that renders themmore susceptible to infections (Canonne-Hergaux et al., 1999; Fritsche et al., 2012; Loomis et al., 2014; Powell and Frelinger, 2017; Soe-Lin et al., 2009).”
Discovery and characterization of a unique mycobacterial heme acquisition system
Tullius, M. V., Harmston, C. A., Owens, C. P., Chim, N., Morse, R. P., McMath, L. M., Iniguez, A., Kimmey, J. M., Sawaya, M. R., Whitelegge, J. P., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009516108 · Cited by 199 · see citing works
Host resistance factor SLC11A1 restricts <i>Salmonella</i> growth through magnesium deprivation
Cunrath, O., & Bumann, D. (2019) · Science · doi:10.1126/science.aax7898 · Cited by 177 · see citing works
The Role of Iron in the Immune Response to Bacterial Infection
Cherayil, B. J. (2011) · Immunologic Research · doi:10.1007/s12026-010-8199-1 · Cited by 191 · see citing works
Miao, R., Fang, X., Zhang, Y., Wei, J., Zhang, Y., & Tian, J. (2023) · Cell Death & Disease · doi:10.1038/s41419-023-05708-0 · Cited by 192 · see citing works
“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1944-8 · Cited by 178 · see citing works
Specific iron chelators determine the route of ferritin degradation
De Domenico, I., Ward, D. M., & Kaplan, J. (2009) · Blood · doi:10.1182/blood-2009-05-224188 · Cited by 176 · see citing works
Iron and Immunity: Immunological Consequences of Iron Deficiency and Overload
Cherayil, B. J. (2010) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-010-0095-9 · Cited by 170 · see citing works
Nramp1 and Other Transporters Involved in Metal Withholding during Infection
Wessling-Resnick, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.643973 · Cited by 136 · see citing works
Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis
Diaz-Ochoa, V. E., Jellbauer, S., Klaus, S., & Raffatellu, M. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2014.00002 · Cited by 129 · see citing works
Iron and innate antimicrobial immunity-depriving the pathogen, defending the host
Nairz, M., Dichtl, S., Schroll, A., Haschka, D., Tymoszuk, P., Theurl, I., & Weiss, G. (2018) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2018.03.007 · Cited by 123 · see citing works
Núñez, G., Sakamoto, K., & Soares, M. P. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800325 · Cited by 115 · see citing works
‘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 · see citing works
Fritsche, G., Nairz, M., Libby, S. J., Fang, F. C., & Weiss, G. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.1111554 · Cited by 72 · see citing works
Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling
Soe-Lin, S., Apte, S. S., Mikhael, M. R., Kayembe, L. K., Nie, G., & Ponka, P. (2010) · Experimental Hematology · doi:10.1016/j.exphem.2010.04.003 · Cited by 69 · see citing works
Self-citationMobilization of iron from ferritin: New steps and details
La, A., Nguyen, T., Tran, K., Sauble, E., Tu, D., Gonzalez, A., Kidane, T. Z., Soriano, C., Morgan, J., Doan, M., et al. (2018) · Metallomics · doi:10.1039/c7mt00284j · Cited by 56 · see citing works
Iron in intracellular infection: to provide or to deprive?
Silva-Gomes, S., Vale-Costa, S., Appelberg, R., & Gomes, M. S. (2013) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00096 · Cited by 51 · see citing works
Owens, C. P., Chim, N., & Goulding, C. W. (2013) · Future Medicinal Chemistry · doi:10.4155/fmc.13.109 · Cited by 50 · see citing works
(2012) · Current Topics in Membranes · doi:10.1016/b978-0-12-394390-3.00010-0 · Cited by 47 · see citing works
The role of endocytic pathways in cellular uptake of plasma non-transferrin iron
Sohn, Y.-S., Ghoti, H., Breuer, W., Rachmilewitz, E., Attar, S., Weiss, G., & Cabantchik, Z. I. (2012) · Haematologica · doi:10.3324/haematol.2011.054858 · Cited by 44 · see citing works
Frazer, D. M., Wilkins, S. J., Darshan, D., Badrick, A. C., McLaren, G. D., & Anderson, G. J. (2012) · British Journal of Haematology · doi:10.1111/j.1365-2141.2012.09104.x · Cited by 43 · see citing works
Theurl, M., Nairz, M., Schroll, A., Sonnweber, T., Asshoff, M., Haschka, D., Seifert, M., Willenbacher, W., Wilflingseder, D., Posch, W., et al. (2014) · Haematologica · doi:10.3324/haematol.2013.099481 · Cited by 42 · see citing works
Hsu, J. L., Manouvakhova, O. V., Clemons, K. V., Inayathullah, M., Tu, A. B., Sobel, R. A., Tian, A., Nazik, H., Pothineni, V. R., Pasupneti, S., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aag2616 · Cited by 38 · see citing works
Rodrigues, P. N., Gomes, S. S., Neves, J. V., Gomes-Pereira, S., Correia-Neves, M., Nunes-Alves, C., Stolte, J., Sanchez, M., Appelberg, R., Muckenthaler, M. U., et al. (2011) · Immunobiology · doi:10.1016/j.imbio.2011.04.004 · Cited by 31 · see citing works
Iron metabolism: microbes, mouse, and man
Latunde‐Dada, G. O. (2009) · BioEssays · doi:10.1002/bies.200900101 · Cited by 29 · see citing works
Nutritional Immunity: Homology Modeling of Nramp Metal Import
Cellier, M. F. M. (2012) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4614-0106-3_19 · Cited by 26 · see citing works
Zhao, L., Li, Y., Song, D., Song, Y., Theurl, M., Wang, C., Cwanger, A., Su, G., & Dunaief, J. L. (2014) · The American Journal of Pathology · doi:10.1016/j.ajpath.2014.07.008 · Cited by 25 · see citing works
Investigating the real role of HIF-1 and HIF-2 in iron recycling by macrophages
Mathieu, J. R. R., Heinis, M., Zumerle, S., Delga, S., Le Bon, A., & Peyssonnaux, C. (2014) · Haematologica · doi:10.3324/haematol.2013.102319 · Cited by 22 · see citing works
- Authors
- Soe-Lin, S., Apte, S. S., Andriopoulos, B., Andrews, M. C., Schranzhofer, M., Kahawita, T., Garcia-Santos, D., & Ponka, P.
- Affiliations
- Jewish General Hospital (CA)
- Harvard University (US)
- Montreal Clinical Research Institute (CA)
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada H3T 1E2;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-04-07
- Volume
- 106
- Issue
- 14
- Pages
- 5960-5965
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2667064
- OpenAlex
- W2067125890
- Cited by
- 167
- References
- 16
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 6 · 2023: 10 · 2022: 10 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 10 · 2017: 9 · 2016: 10 · 2015: 9 · 2014: 18 · 2013: 10 · 2012: 12
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- Canadian Institutes of Health Research
- 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
- NRAMP1, ferroportin, DMT1, erythrophagocytosis, iron recycling, macrophages, hemolytic anemia, phenylhydrazine, hepcidin, transferrin saturation, iron overload, hereditary iron overload, splenomegaly, reticulocytosis, liver iron stores
- MeSH terms
- Natural Resistance-associated Macrophage Protein 1, Anemia, Hemolytic, Animals, Erythrocytes, Hemoglobins, Iron, Liver, Macrophages, Phagocytosis, Spleen, Mice, Knockout, Cation Transport Proteins, Mice
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