The DOI matches its Crossref record; 267 of the 269 references it cites were found in a registry or an index; 6 of the 158 sources its claims cite were checked for support.
“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
Open accessAbstract
Macrophages reside in virtually every organ. First arising during embryogenesis, macrophages replenish themselves in the adult through a combination of self-renewal and influx of bone marrow-derived monocytes. As large phagocytic cells, macrophages participate in innate immunity while contributing to tissue-specific homeostatic functions. Among the key metabolic tasks are senescent red blood cell recycling, free heme detoxification, and provision of iron for de novo hemoglobin synthesis. While this systemic mechanism involves the shuttling of iron between spleen, liver, and bone marrow through the concerted function of defined macrophage populations, similar circuits appear to exist within the microenvironment of other organs. The high turnover of iron is the prerequisite for continuous erythropoiesis and tissue integrity but challenges macrophages' ability to maintain cellular iron homeostasis and immune function.This review provides a brief overview of systemic, microenvironmental, and cellular aspects of macrophage iron handling with a focus on exciting and unresolved questions in the field.
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Written from the paper’s full text.
TL;DR
This review synthesizes how macrophages handle iron at systemic, microenvironmental, and cellular levels, emphasizing red blood cell recycling, the hepcidin–ferroportin axis, and local iron circuits in organs such as liver, spleen, muscle, heart, vessels, brain, retina, bone, and bone marrow. It argues that macrophage iron homeostasis is central to erythropoiesis, tissue integrity, and immunity, while many mechanistic questions remain unresolved.
Key findings
- Systemic iron homeostasis depends on macrophage recycling of senescent red blood cells: 20–25 mg/day of iron is needed for new RBC production, dietary absorption supplies only 1–2 mg/day, the adult Hb iron pool is 1500–2500 mg, RBC lifespan averages 120 days, and splenic red pulp macrophages clear more than 2 × 10⁶ RBC per second in a healthy adult.
- The hepcidin–ferroportin-1 (Fpn1) axis is central: hepatocyte-derived hepcidin targets Fpn1 for degradation, reducing iron transfer from macrophages and the diet into plasma; macrophage iron handling is further controlled by Bach1/Nrf2, SpiC, HIFs, IRPs, Hmox1, Flvcr, and Nramp1.
- Local iron-recycling circuits exist beyond the spleen and liver: liver Kupffer cells dominate clearance during excessive RBC damage and recruit CCR2⁺ monocytes via CCL2/CCL3; muscle injury involves myoglobin (17 kDa, below the kidney’s 30–50 kDa filtration cutoff); and analogous macrophage iron handling is discussed in heart, atherosclerotic plaques, brain microglia, retina, osteoclasts, and bone marrow erythroid islands.
- Macrophage iron overload impairs antimicrobial immunity: iron inhibits NF-IL6 and HIF-1α binding, blocks Nos2/NO formation, and promotes ROS/NF-κB, while IRP1/IRP2 deletion impairs control of Salmonella Typhimurium.
Methods
- Narrative review; no primary experiments, systematic search strategy, or meta-analysis are described.
- Synthesizes published literature and includes a table of selected macrophage iron-handling proteins and figures on systemic and cellular iron pathways.
- Main analysis is conceptual and mechanistic synthesis across systemic, organ-level, and cellular contexts.
Limitations
- Stated: many unresolved questions remain, including mechanistic insight into atherosclerosis, brain iron handling, and iron shuttling from erythroid island macrophages to erythroblasts; findings from small animal models need translation to humans.
- Stated: some areas are controversial, such as the role of Kupffer cells in hepcidin regulation and the directionality of Nramp1 iron transport.
- Evident: as a narrative review, it lacks systematic inclusion criteria and primary data, so conclusions depend on selected cited literature and may reflect selection bias.
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Figures
![Fig. 1 a In steady state, 20–25 mg/day of iron is needed to generate new red blood cells (RBC) in the bone marrow (depicted as vertebral body). The RBC of an adult human form the body’s largest iron pool (1500–2500 mg contained in hemoglobin [Hb]). After an average lifetime of 120 days, aged RBC (aRBC) are trapped in the spleen, recognized by red pulp macrophages (RPM), and eliminated. Their Hb is recycled, and ferroportin (Fpn)-1 exports iron into sinusoidal capillaries where it is loaded onto transferrin (TF). TF-bound iron is utilized by developing erythroblasts (EB) via TF receptor (Tfr)-1. Erythroid island macrophages assist in iron uptake and differentiation. Plasma iron content is sensed by hepatocytes, presumably via Tfr1 and other iron-sensitive molecules. They affect the transcriptional activation of hepcidin, the major iron hormone, in hepatocytes. Hepcidin acts as negative feedback regulator of iron influx by targeting Fpn1 resulting in degradation of the latter and thus reduction of iron transfer from the diet and macrophages to the plasma. Kupffer cells (KC) inhibit hepcidin expression by hepatocytes and also engage in erythrophagocytosis. b The lifespan of RBC can be reduced as a consequence of autoinflammation and subsequent hemolysis, radical formation and toxin activity or based on intrinsic structural or metabolic defects. The rapid accumulation of damaged RBC (dRBC) may overwhelm the spleen’s clearance capacity. In such a scenario, KC engulf dRBC which may result in cell death. As back-up system, monocytes are recruited from the bone marrow and possibly spleen via chemokines CCL2 and CCL3 and their receptor CCR2. These monocytes encounter a niche in the liver and differentiate into KC-like cells that express Fpn1 which is induced by several mechanisms including the growth factor macrophage colony-stimulating factor (M-CSF). Fpn1-mediated iron export sustains increased erythropoiesis in the bone marrow to compensate for losses by RBC damage](/paper-figures/0e88f11d64624add91b4a404b7999c03/pumping-ironhow-macrophages-handle-iron-at-the-systemic-microenvironmental-and-figure-1.jpg)
Verification
Claims the paper makes
91 Not checked yet · 19 Own interpretation · 2 Partly supported · 1 Supported · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is well established that RPM and KC express the complete machinery for RBC clearance and heme iron recycling [72, 88, 231].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > A broad spectrum of iron uptake pathways
What the sources say
- Partly supportedcites [72] Franken L, Klein M, Spasova M, Elsukova A, Wiedwald U, Welz M, Knolle P, Farle M, Limmer A, Kurts C (2015) Splenic red pulp macrophages are intrinsically superparamagnetic and contaminate magnetic cell isolates. Sci Rep 5:12940 sourceExperimental — accuracy not yet measured
The Results (‘RPM are superparamagnetic’) identify degradation of aged or damaged erythrocytes as a main RPM function, and ‘Functional consequences of RPM contaminations’ identifies iron-metabolism genes active in RPM. The Results (‘Kupffer cells also show superparamagnetic behavior’) say Kupffer cells can take over erythrocyte degradation when RPM are absent. The paper does not establish that both cell types express the complete machinery for RBC clearance and heme-iron recycling. (LLM, conf=0.87)
- Partly supportedcites [88] Haldar M, Kohyama M, So AY, Kc W, Wu X, Briseno CG, Satpathy AT, Kretzer NM, Arase H, Rajasekaran NS, Wang L, Egawa T, Igarashi K, Baltimore D, Murphy TL, Murphy KM (2014) Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156:1223–1234 sourceExperimental — accuracy not yet measured
The Introduction says red pulp macrophages (RPM), and to some extent liver macrophages, clear erythrocytes, degrade heme, and release its iron. It does not establish that both RPM and Kupffer cells (KC) express the complete machinery for those processes; its qualification of the liver macrophages is narrower than the claim. (LLM, conf=0.86)
- Partly supportedcites [231] Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK (2016a) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945–951 sourceExperimental — accuracy not yet measured
The paper reports that Kupffer cells (KC) and red pulp macrophages (RPM) express surface ferroportin for iron transport, and that the liver and spleen express ferritin and ferroportin at steady state (body text indexed under Abstract; page unavailable). This supports their involvement in iron recycling, but does not establish that both cell types express the complete machinery for RBC clearance and heme iron recycling. The paper also reports that clearing stressed RBCs under increased demand requires transient liver macrophages. (LLM, conf=0.84)
boosted- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Two elegant studies have shown that the application of nanoparticles to tumor-bearing mice is sufficient to induce clinical remission.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
What the sources say
- Partly supportedcites [112] Kim SE, Zhang L, Ma K, Riegman M, Chen F, Ingold I, Conrad M, Turker MZ, Gao M, Jiang X, Monette S, Pauliah M, Gonen M, Zanzonico P, Quinn T, Wiesner U, Bradbury MS, Overholtzer M (2016) Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol 11:977–985 sourceExperimental — accuracy not yet measured
The “αMSH-PEG-C′ dots inhibit tumor growth” section reports that nanoparticles inhibited growth in tumor-bearing mice and caused partial HT-1080 tumor regression. It reports neither complete tumor disappearance nor clinical remission, so the claimed outcome overstates the finding. (LLM, conf=0.90)
- Partly supportedcites [257] Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, Pajarinen JS, Nejadnik H, Goodman S, Moseley M, Coussens LM, Daldrup-Link HE (2016) Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol 11:986–994 sourceExperimental — accuracy not yet measured
The Results section, “Inhibition of metastases in the liver and lungs” (page unavailable), reports that ferumoxytol given to mice with confirmed tumours significantly reduced tumour signals and tumour load. It does not report clinical remission. The mammary-tumour Results likewise report inhibited growth, not remission. (LLM, conf=0.89)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
In the paper
“However, when the capacity of red pulp macrophages (the iron-recycling macrophage population in the spleen, henceforward abbreviated as RPM) and KC is overwhelmed, the cells die, presumably by a specific form of cell death called ferroptosis that is induced by iron-mediated oxidative stress and lipid peroxidation [54].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
What the sources say
- Not checked yetcites [54] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Second, the degradation of Bach1 induces expression of the transcription factor (an E26 transformation-specific transcription factor of the Spi subfamily) SpiC independently of Nrf2 [116, 211].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling > Erythrophagocytosis
What the sources say
- Not checked yetcites [116] Kohyama M, Ise W, Edelson BT, Wilker PR, Hildner K, Mejia C, Frazier WA, Murphy TL, Murphy KM (2009) Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457:318–321 source
- Not checked yetcites [211] Soares MP, Hamza I (2016) Macrophages and iron metabolism. Immunity 44:492–504 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The maintenance of iron homeostasis at the systemic level requires iron recycling (Fig. 1), much of which is contained in senescent red blood cells (RBC).”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, monocyte recruitment from the BM to the liver is mediated by a liver-specific, KC-derived CC-chemokine gradient of CCL2 and CCL3 that attracts CCR2+ CCR5+ monocytes to the organ.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
What the sources say
- Not checked yetcites [231] Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK (2016a) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945–951 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“HIF-HRE interaction in response to hypoxia thus stimulates iron release from macrophages by inducing Hmox1 and Fpn1 as well as one of its associated ferroxidases, ceruloplasmin [37, 63, 200].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling > Erythrophagocytosis
What the sources say
- Not checked yetcites [37] Chiabrando D, Fiorito V, Marro S, Silengo L, Altruda F, Tolosano E (2012) Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice. Blood Cells Mol Dis 50:25–30 source
- Not checked yetcites [63] Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, Harris AL, Johnson RS, Imityaz HZ, Simon MC, Fredlund E, Greten FR, Rius J, Lewis CE (2009) Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114:844–859 source
- Not checked yetcites [200] Sarkar J, Seshadri V, Tripoulas NA, Ketterer ME, Fox PL (2003) Role of ceruloplasmin in macrophage iron efflux during hypoxia. J Biol Chem 278:44018–44024 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This chemokine-mediated monocyte recruitment is essential because if disrupted pharmacologically, damaged RBC accumulate in glomerular capillaries resulting in renal failure [231].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
What the sources say
- Not checked yetcites [231] Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK (2016a) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945–951 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The liver acts as central orchestrator of iron metabolism through various mechanisms.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Liver—the iron regulatory organ
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In conditions of excessive RBC damage, liver macrophages (Kupffer cells, henceforward abbreviated as KC) dominate RBC clearance (as detailed in “Liver—the iron regulatory organ” section) [231].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
What the sources say
- Not checked yetcites [231] Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK (2016a) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945–951 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 45
- Probably not a substantial claim. 8
- The quote only partly states this claim. 1
Every source the paper cites for this claim was checked and supports it.
In the paper
“For instance, EIM express the αV integrin which binds ICAM4 on erythroid cells, and ICAM4 KO mice have reduced numbers of erythropoietic islands [126].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone marrow—are erythroblasts “nursed” with iron?
What the sources say
- Supportedcites [126] Lee G, Lo A, Short SA, Mankelow TJ, Spring F, Parsons SF, Yazdanbakhsh K, Mohandas N, Anstee DJ, Chasis JA (2006) Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation. Blood 108:2064–2071 source
The Introduction describes erythroid ICAM-4 binding to macrophage αV integrins, and the Abstract reports αV integrin expression in macrophages isolated from erythroblastic islands. The Results section, “Erythroblastic islands formed in vivo are decreased in ICAM-4 null mice,” reports 64% fewer islands in knockout mice than in wild-type littermates. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
None of the sources cited for this claim have been checked yet.
In the paper
“The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators [171, 229].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
What the sources say
- Not checked yetcites [171] Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342 source
- Not checked yetcites [229] Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G (2009) Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 113:5277–5286 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The molecular machinery of RBC recycling is relatively well described, and its function is essential to tissue integrity given the pro-oxidative capacity of free labile heme.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling > Erythrophagocytosis
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It is at this location that ferroportin-1 (Fpn1; AKA solute carrier family 40 member 1) fulfills its function as the sole cellular efflux protein for ionic iron, shuttling apically absorbed iron to the circulation, where it is oxidized and loaded onto transferrin (TF) [173].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
What the sources say
- Not checked yetcites [173] Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004b) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It is essential to the development of these cell types as Spic −/− mice have drastically reduced numbers of RPM and EIM which lead to reduced proerythroblast numbers in the steady state, supporting the idea that iron recycling is essential to sustain iron-sufficient erythropoiesis [58].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling > Erythrophagocytosis
What the sources say
- Not checked yetcites [58] Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR (2005) Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 106:1092–1097 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, the inflammasome activation via cryopyrin (AKA NLRP3) is sensitive to surplus intracellular heme while extracellular free heme can activate Toll-like receptor 4 (TLR4), supporting the idea that free heme is an endogenous danger signal [60, 65, 66, 131].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling > Erythrophagocytosis
What the sources say
- Not checked yetcites [60] Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, Zamboni DS, Bozza MT (2014) Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci U S A 111:E4110–E4118 source
- Not checked yetcites [65] Fernandez PL, Dutra FF, Alves L, Figueiredo RT, Mourao-Sa D, Fortes GB, Bergstrand S, Lonn D, Cevallos RR, Pereira RM, Lopes UG, Travassos LH, Paiva CN, Bozza MT (2010) Heme amplifies the innate immune response to microbial molecules through spleen tyrosine kinase (Syk)-dependent reactive oxygen species generation. J Biol Chem 285:32844–32851 source
- Not checked yetcites [66] Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, Oliveira MF, Oliveira PL, Graca-Souza AV, Bozza MT (2007) Characterization of heme as activator of Toll-like receptor 4. J Biol Chem 282:20221–20229 source
- Not checked yetcites [131] Li Q, Fu W, Yao J, Ji Z, Wang Y, Zhou Z, Yan J, Li W (2014a) Heme induces IL-1beta secretion through activating NLRP3 in kidney inflammation. Cell Biochem Biophys 69:495–502 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, their roles in the metabolic activity of the adjacent myocardium and in chronic cardiac diseases such as congestive heart failure are increasingly appreciated [199], and macrophages may either tailor the delivery of iron to the myocardium or accumulate and detoxify heme which may mainly arise from tissue injury [161, 214].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Heart—an organ exquisitely sensitive to iron toxicity
What the sources say
- Not checked yetcites [161] Nahrendorf M, Swirski FK (2016) Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J 37:868–872 source
- Not checked yetcites [214] Sohn YS, Ghoti H, Breuer W, Rachmilewitz E, Attar S, Weiss G, Cabantchik ZI (2012) The role of endocytic pathways in cellular uptake of plasma non-transferrin iron. Haematologica 97:670–678 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Although iron-mediated generation of ROS and injury to mitochondria are likely mechanisms [196, 204]”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
What the sources say
- Not checked yetcites [196] Rouault TA (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14:551–564 source
- Not checked yetcites [204] Schipper HM (1999) Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases. Neurotox Res 1:57–70 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A paradigmatic yet rare NBIA condition is the neuroferritinopathy that is caused by a mutation in the coding region of the FTL gene [44, 45].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
What the sources say
- Not checked yetcites [44] Cozzi A, Santambrogio P, Privitera D, Broccoli V, Rotundo LI, Garavaglia B, Benz R, Altamura S, Goede JS, Muckenthaler MU, Levi S (2013) Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome. J Exp Med 210:1779–1791 source
- Not checked yetcites [45] Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28:350–354 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It would appear that neuronal iron efflux is insufficient to remove surplus and potentially harmful iron from the cytoplasm.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Müller glial cells and endothelial cells of the retina both express Fpn1, but only the latter cell type is sensitive to hepcidin regulation.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Retina—the location in which iron aggravates light damage
What the sources say
- Not checked yetcites [232] Theurl M, Song D, Clark E, Sterling J, Grieco S, Altamura S, Galy B, Hentze M, Muckenthaler MU, Dunaief JL (2016b) Mice with hepcidin-resistant ferroportin accumulate iron in the retina. FASEB J 30:813–823 source
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In the paper
“Arthropathy of the second and third metacarpophalangeal joints is a typical manifestation of type I hemochromatosis [94].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone—osteoclasts are iron-dependent
What the sources say
- Not checked yetcites [94] Heiland GR, Aigner E, Dallos T, Sahinbegovic E, Krenn V, Thaler C, Weiss G, Distler JH, Datz C, Schett G, Zwerina J (2010) Synovial immunopathology in haemochromatosis arthropathy. Ann Rheum Dis 69:1214–1219 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, LDN treatment also reduced atherosclerotic lesion size, suggesting that modulating systemic iron metabolism affects atherosclerosis progression.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Blood vessels—arterial macrophage iron overload as hallmark of atherosclerosis
What the sources say
- Not checked yetcites [198] Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, Davis T, Rostad B, Pachura K, Adams L, Elliott J, Taylor WR, Narula J, Kolodgie F, Virmani R, Hong CC, Finn AV (2012) Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol 32:299–307 source
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In the paper
“In addition, experimental light damage to the retina results in microglial activation, its migration to the outer retina, and in induction of FT H and L chains.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Retina—the location in which iron aggravates light damage
What the sources say
- Not checked yetcites [217] Song D, Song Y, Hadziahmetovic M, Zhong Y, Dunaief JL (2012a) Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina. Free Radic Biol Med 53:64–71 source
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In the paper
“Notably, Lcn2 also affects a variety of brain functions from cognition to emotional stress [104].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
What the sources say
- Not checked yetcites [104] Jha MK, Lee S, Park DH, Kook H, Park KG, Lee IK, Suk K (2014) Diverse functional roles of lipocalin-2 in the central nervous system. Neurosci Biobehav Rev 49:135–156
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For instance, after experimental intracranial hemorrhage (ICH), microglia clear RBC but may also sustain inflammation and cause secondary damage.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“However, microglia are also exquisitely sensitive to the potential toxicity of IONs because they are rapidly degraded within lysosomes and their iron catalyzes ROS generation [184].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
What the sources say
- Not checked yetcites [184] Petters C, Thiel K, Dringen R (2015) Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes. Nanotoxicology 10:332–342 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Since photoreceptors are sensitive to iron toxicity, local iron regulatory circuits including the hepcidin-Fpn1 axis operate in the retina [261].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Retina—the location in which iron aggravates light damage
What the sources say
- Not checked yetcites [261] Zhao L, Li Y, Song D, Song Y, Theurl M, Wang C, Cwanger A, Su G, Dunaief JL (2014) A high serum iron level causes mouse retinal iron accumulation despite an intact blood-retinal barrier. Am J Pathol 184:2862–2867 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the retina is another organ that is sensitive to iron toxicity but has evidence of endogenous mechanisms to maintain local iron homeostasis in the microenvironment.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Retina—the location in which iron aggravates light damage
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The composition of FT is cell type-specific, and central neuronal FT are L chain-rich [236].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
What the sources say
- Not checked yetcites [236] Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99:3505–3516 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, the hyperferritinemia-cataract syndrome that is caused by a mutation in a specific non-coding region of the FTL gene, the iron-responsive element (IRE), is not associated with iron accumulation in the brain but with the formation of ferritin crystals in the ocular lenses, resulting in cataracts in early adulthood [23, 83, 195].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Brain—cerebral iron overload is implicated in neurodegeneration
What the sources say
- Not checked yetcites [23] Brooks DG, Manova-Todorova K, Farmer J, Lobmayr L, Wilson RB, Eagle RC Jr, St Pierre TG, Stambolian D (2002) Ferritin crystal cataracts in hereditary hyperferritinemia cataract syndrome. Invest Ophthalmol Vis Sci 43:1121–1126
- Not checked yetcites [83] Girelli D, Corrocher R, Bisceglia L, Olivieri O, De Franceschi L, Zelante L, Gasparini P (1995) Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”). Blood 86:4050–4053 source
- Not checked yetcites [195] Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2:406–414 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Osteoclast precursors take up iron via Tfr1 and utilize six-transmembrane epithelial antigen of prostate (Steap4) as ferrireductase [262].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone—osteoclasts are iron-dependent
What the sources say
- Not checked yetcites [262] Zhou J, Ye S, Fujiwara T, Manolagas SC, Zhao H (2013) Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation. J Biol Chem 288:30064–30074 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“An increase in plasma iron stimulates hepcidin secretion which dampens macrophage iron egress and to a lesser extent duodenal iron absorption following its interaction with Fpn1.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Liver—the iron regulatory organ
What the sources say
- Not checked yetcites [158] Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, Melse-Boonstra A, Brittenham G, Swinkels DW, Zimmermann MB (2015) Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 126:1981–1989 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It is well characterized that erythroblasts expel their nuclei during differentiation and that these are taken up by EIM after phosphatidylserine exposure via Tim4 and MER proto-oncogene, tyrosine kinase (MerTK) [234, 254].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone marrow—are erythroblasts “nursed” with iron?
What the sources say
- Not checked yetcites [234] Toda S, Segawa K, Nagata S (2014) MerTK-mediated engulfment of pyrenocytes by central macrophages in erythroblastic islands. Blood 123:3963–3971 source
- Not checked yetcites [254] Yoshida H, Kawane K, Koike M, Mori Y, Uchiyama Y, Nagata S (2005) Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature 437:754–758 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“At either location, Dmt1 only accepts ferrous iron along with other divalent cations, such as copper or manganese, and co-localizes with an iron reductase [152, 177].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > A broad spectrum of iron uptake pathways
What the sources say
- Not checked yetcites [152] McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291:1755–1759 source
- Not checked yetcites [177] Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD (2005) Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37:1264–1269 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These are best characterized in bacteria, but eukaryotes including fungi and mammals produce siderophores, too [16, 42, 67, 86, 106].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level
What the sources say
- Not checked yetcites [16] Behnsen J, Raffatellu M (2016) Siderophores: more than stealing iron. MBio 7:e01397–16 source
- Not checked yetcites [42] Correnti C, Strong RK (2012) Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool. J Biol Chem 287:13524–13531 source
- Not checked yetcites [67] Fischbach MA, Lin H, Liu DR, Walsh CT (2006) How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol 2:132–138 source
- Not checked yetcites [86] Haas H (2014) Fungal siderophore metabolism with a focus on Aspergillus fumigatus. Nat Prod Rep 31:1266–1276 source
- Not checked yetcites [106] Jones RL, Peterson CM, Grady RW, Cerami A (1980) Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth. J Exp Med 151:418–428 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, membrane VCAM1 is expressed on CD169+ macrophages in the spleen and provides a molecular anchor to retain hematopoietic stem cells in the murine spleen, although it is unclear whether this is also relevant to arthropathy [61].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone—osteoclasts are iron-dependent
What the sources say
- Not checked yetcites [61] Dutta P, Hoyer FF, Grigoryeva LS, Sager HB, Leuschner F, Courties G, Borodovsky A, Novobrantseva T, Ruda VM, Fitzgerald K, Iwamoto Y, Wojtkiewicz G, Sun Y, Da Silva N, Libby P, Anderson DG, Swirski FK, Weissleder R, Nahrendorf M (2015) Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. J Exp Med 212:497–512 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“At the cell surface membrane, macrophages possess the heme exporter Flvcr and its genetic deletion results in RPM iron overload [108].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > A broad spectrum of iron uptake pathways
What the sources say
- Not checked yetcites [108] Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, Kingsley PD, De Domenico I, Vaughn MB, Kaplan J, Palis J, Abkowitz JL (2008) A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319:825–828 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, the functions of IRPs1 and 2 are redundant in macrophages and only targeted deletion of both isoforms via the LysM-Cre system results in increased FT levels and intracellular iron retention [193].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > The control of cytosolic iron levels
What the sources say
- Not checked yetcites [193] Recalcati S, Alberghini A, Campanella A, Gianelli U, De Camilli E, Conte D, Cairo G (2006) Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. Haematologica 91:303–310
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Of interest, circulating VCAM1 is shed by the metalloproteinase ADAM metallopeptidase domain 17 (ADAM17, AKA TNF alpha-converting enzyme (TACE)) which is activated by inflammatory stimuli [81].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone—osteoclasts are iron-dependent
What the sources say
- Not checked yetcites [81] Garton KJ, Gough PJ, Philalay J, Wille PT, Blobel CP, Whitehead RH, Dempsey PJ, Raines EW (2003) Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17). J Biol Chem 278:37459–37464 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Its two major functional components are HRG1 which shifts heme from the endosome/lysosome to the cytoplasm and Hmox1 which then metabolizes heme [117].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level
What the sources say
- Not checked yetcites [117] Korolnek T, Hamza I (2014) Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front Pharmacol 5:126 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the deletion of Fpn1 by Cre recombinase expressed under the lysozyme M promoter results in iron accumulation in macrophages, including BM macrophages, and mild anemia.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone marrow—are erythroblasts “nursed” with iron?
What the sources say
- Not checked yetcites [259] Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B, Nie G, Knutson MD, Anderson GJ, Wang F (2011) Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118:1912–1922 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“However, LysM-Cre FTH mice have no apparent phenotype suggesting that iron storage and trafficking are well controlled in myeloid cells by other mechanisms [46, 239].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > The control of cytosolic iron levels
What the sources say
- Not checked yetcites [46] Darshan D, Vanoaica L, Richman L, Beermann F, Kuhn LC (2009) Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage. Hepatology 50:852–860 source
- Not checked yetcites [239] Vanoaica L, Darshan D, Richman L, Schumann K, Kuhn LC (2010) Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab 12:273–282 source
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This suggests that EIM utilize Fpn1 to export iron and thus function as iron-rich nurse cells [259].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone marrow—are erythroblasts “nursed” with iron?
What the sources say
- Not checked yetcites [259] Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B, Nie G, Knutson MD, Anderson GJ, Wang F (2011) Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118:1912–1922 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Tfr1, which is also known as CD71, is widely expressed by isolated macrophages, and it may form a major route of iron uptake in the absence of RBC (an indirect iron source), though it also appears to be important in adaptive immunity [103, 138].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > A broad spectrum of iron uptake pathways
What the sources say
- Not checked yetcites [103] Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet 48:74–78 source
- Not checked yetcites [138] Ludwiczek S, Aigner E, Theurl I, Weiss G (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101:4148–4154 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“While some of these compounds such as citrate are ubiquitous substrates, other mammalian siderophores such as catechols are probably synthesized from commensal metabolites or dietary precursors [11, 50, 252].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level
What the sources say
- Not checked yetcites [11] Bao G, Clifton M, Hoette TM, Mori K, Deng SX, Qiu A, Viltard M, Williams D, Paragas N, Leete T, Kulkarni R, Li X, Lee B, Kalandadze A, Ratner AJ, Pizarro JC, Schmidt-Ott KM, Landry DW, Raymond KN, Strong RK, Barasch J (2010) Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol 6:602–609 source
- Not checked yetcites [50] Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:1006–1017 source
- Not checked yetcites [252] Xiao X, Yeoh BS, Saha P, Tian Y, Singh V, Patterson AD, Vijay-Kumar M (2016) Modulation of urinary siderophores by the diet, gut microbiota and inflammation in mice. J Nutr Biochem 41:25–33 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The transcription factor SpiC and its down-stream effector Hmox1 are both essential for EIM differentiation, since ablation of either gene reduces EIM number [73, 88].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Bone marrow—are erythroblasts “nursed” with iron?
What the sources say
- Not checked yetcites [73] Fraser ST, Midwinter RG, Coupland LA, Kong S, Berger BS, Yeo JH, Andrade OC, Cromer D, Suarna C, Lam M, Maghzal GJ, Chong BH, Parish CR, Stocker R (2015) Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice. Haematologica 100:601–610 source
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plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Dmt1 shifts iron from the extracellular space to the cytoplasm and, in its alternately spliced form, from the Tfr1 endosome to the cytoplasm [69, 99, 139].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > A broad spectrum of iron uptake pathways
What the sources say
- Not checked yetcites [69] Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci U S A 95:1148–1153 source
- Not checked yetcites [99] Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A 99:12345–12350 source
- Not checked yetcites [139] Ludwiczek S, Theurl I, Muckenthaler MU, Jakab M, Mair SM, Theurl M, Kiss J, Paulmichl M, Hentze MW, Ritter M, Weiss G (2007) Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med 13:448–454 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This pathogen preferentially infects murine macrophages and has a proliferative advantage in the absence of both IRPs resulting in increased bacterial burden and reduced survival in a systemic infection model.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > The control of cytosolic iron levels
What the sources say
- Not checked yetcites [166] Nairz M, Ferring-Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A, Haschka D, Fang FC, Hentze MW, Weiss G, Galy B (2015a) Iron regulatory proteins mediate host resistance to salmonella infection. Cell Host Microbe 18:254–261 source
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In the paper
“The deletion of both IRPs in macrophages does not affect RBC recycling but impairs their nutritional immune functions against intracellular bacteria, such as Salmonella Typhimurium [166].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > The control of cytosolic iron levels
What the sources say
- Not checked yetcites [166] Nairz M, Ferring-Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A, Haschka D, Fang FC, Hentze MW, Weiss G, Galy B (2015a) Iron regulatory proteins mediate host resistance to salmonella infection. Cell Host Microbe 18:254–261 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Macrophages express a range of factors mediating iron uptake (summarized in the Table 1) which essentially face only two pathways for iron efflux, Fpn1 for ionic iron and feline leukemia virus subtype C receptor (Flvcr) for heme iron (Fig. 2), although alternatives routes may exist [49, 136].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level
What the sources say
- Not checked yetcites [49] Devireddy LR, Gazin C, Zhu X, Green MR (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123:1293–1305 source
- Not checked yetcites [136] Lok HC, Sahni S, Jansson PJ, Kovacevic Z, Hawkins CL, Richardson DR (2016) A nitric oxide storage and transport system that protects activated macrophages from endogenous nitric oxide cytotoxicity. J Biol Chem 291:27042–27061 source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Second, iron alters gene transcription, translation, and mitochondrial respiration in macrophages [165, 175].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
What the sources say
- Not checked yetcites [165] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5:152 source
- Not checked yetcites [175] Oexle H, Gnaiger E, Weiss G (1999) Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta 1413:99–107 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast to its inhibitory effect on NO, iron stimulates the non-enzymatic generation of ROS which may promote their antimicrobial activity but contribute to tissue damage and the pathogenesis of many inflammatory disorders.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
What the sources say
- Not checked yetcites [213] Soe-Lin S, Apte SS, Andriopoulos B Jr, Andrews MC, Schranzhofer M, Kahawita T, Garcia-Santos D, Ponka P (2009) Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci U S A 106:5960–5965 source
- Not checked yetcites [31] Cellier MF (2012) Nramp: from sequence to structure and mechanism of divalent metal import. Curr Top Membr 69:249–293 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These effects may contribute to the inflammatory characteristics of sickle cell disease and can be ameliorated by the heme scavenger HPX.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, the functional form of Nramp1 in myeloid cells shifts the balance in T helper cell activity towards Th1, which may increase resistance to infections while increasing the susceptibility to autoimmune diseases [167, 226].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
What the sources say
- Not checked yetcites [167] Nairz M, Schroll A, Demetz E, Tancevski I, Theurl I, Weiss G (2015b) 'Ride on the ferrous wheel'—the cycle of iron in macrophages in health and disease. Immunobiology 220:280–294 source
- Not checked yetcites [226] Theurl I, Fritsche G, Ludwiczek S, Garimorth K, Bellmann-Weiler R, Weiss G (2005) The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals 18:359–367 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Another layer of complexity is added by the fact that TLR4 signaling stabilizes HIF-1α activation via induction of FTH and hypoxia stimulates arginase-1 expression in myeloid cells thus undermining Leishmania killing [142, 209].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
What the sources say
- Not checked yetcites [142] Mahnke A, Meier RJ, Schatz V, Hofmann J, Castiglione K, Schleicher U, Wolfbeis OS, Bogdan C, Jantsch J (2014) Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages. J Invest Dermatol 134:2339–2346 source
- Not checked yetcites [209] Siegert I, Schodel J, Nairz M, Schatz V, Dettmer K, Dick C, Kalucka J, Franke K, Ehrenschwender M, Schley G, Beneke A, Sutter J, Moll M, Hellerbrand C, Wielockx B, Katschinski DM, Lang R, Galy B, Hentze MW, Koivunen P, Oefner PJ, Bogdan C, Weiss G, Willam C, Jantsch J (2015) Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1alpha upon LPS activation in the presence of ample oxygen. Cell Rep 13:2048–2055 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The other study suggested that IONs stimulate TNF expression while inhibiting arginase-1 which results in improved killing of tumor cells [257].”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
What the sources say
- Not checked yetcites [257] Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, Pajarinen JS, Nejadnik H, Goodman S, Moseley M, Coussens LM, Daldrup-Link HE (2016) Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol 11:986–994 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mechanistically, these two modes of HIF activation are distinct. While TLR4 signaling results in depletion of iron as co-substrate which prolyl hydroxylases (PHDs) require to tag HIF for degradation, hypoxia, per definition, impairs PHD activity due to a lack of their substrate oxygen.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > The complexity of macrophage iron handling at the cellular level > Interplay of macrophage iron metabolism and immune functions
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Under physiologic conditions, macrophages recycle the iron for erythropoiesis, while under hemolytic stress, macrophages detoxify heme to prevent iron toxicity towards parenchymal cells and tissues.”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper relies on this without support.
No regulated pathway of iron excretion exists in the mammalian organism.
“It is generally thought that no regulated pathway of iron excretion exists in the mammalian organism.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Furthermore, free heme and hemoglobin released during red blood cell (RBC) lysis are bound in the circulation by hemopexin and haptoglobin, respectively, and these iron-containing complexes are then taken up by cells expressing the CD91 and CD163 receptors (Nairz et al., 2017).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
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In the paper
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Systemic aspects of iron recycling
“circulating hemoglobin (Hb) and heme are bound by hemopexin (HPX) and haptoglobin, respectively”
§ “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels > Local circuits > Liver—the iron regulatory organ
“Haptoglobin and HPX scavenge free Hb and heme, respectively”
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Self-citation
Metadata
- Authors
- Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G.
- Affiliations
- Harvard University (US)
- Innsbruck Medical University (AT)
- Corresponding author
- Nairz, Manfred
- Venue
- Pflügers Archiv - European Journal of Physiology
- Published
- 2017-03-01
- Volume
- 469
- Issue
- 3-4
- Pages
- 397-418
- ISSN
- 0031-6768 (ISSN-L)
- 1432-2013
- PMC
- PMC5362662
- OpenAlex
- W2592213450
- Semantic Scholar
- 223e4460dd3f67b8a384962555fdeab9e69defd4
- Cited by
- 178
- References
- 269
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 15 · 2023: 22 · 2022: 23 · 2021: 28 · 2020: 31 · 2019: 14 · 2018: 17 · 2017: 4
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Pflügers Archiv - European Journal of Physiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- University of Innsbruck and Medical University of Innsbruck
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Physical Sciences › Materials Science › Metals and Alloys › Iron and Steelmaking Processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- macrophages, iron homeostasis, iron metabolism, heme detoxification, hemoglobin synthesis, spleen, liver, bone marrow, tissue microenvironment, innate immunity, erythropoiesis
- MeSH terms
- Animals, Erythropoiesis, Homeostasis, Humans, Iron, Macrophages, Cellular Microenvironment
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