“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels

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].”

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

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.”

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].”

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

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].”

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

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].”

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

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].”

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

In the paper

“Although iron-mediated generation of ROS and injury to mitochondria are likely mechanisms [196, 204]”

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

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].”

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

In the paper

“It would appear that neuronal iron efflux is insufficient to remove surplus and potentially harmful iron from the cytoplasm.”

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.”

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

In the paper

“Arthropathy of the second and third metacarpophalangeal joints is a typical manifestation of type I hemochromatosis [94].”

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

In the paper

“Importantly, LDN treatment also reduced atherosclerotic lesion size, suggesting that modulating systemic iron metabolism affects atherosclerosis progression.”

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

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.”

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

In the paper

“Notably, Lcn2 also affects a variety of brain functions from cognition to emotional stress [104].”

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

In the paper

“For instance, after experimental intracranial hemorrhage (ICH), microglia clear RBC but may also sustain inflammation and cause secondary damage.”

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].”

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

In the paper

“Since photoreceptors are sensitive to iron toxicity, local iron regulatory circuits including the hepcidin-Fpn1 axis operate in the retina [261].”

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

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.”

In the paper

“The composition of FT is cell type-specific, and central neuronal FT are L chain-rich [236].”

What the sources say

• Not checked yetcites [236] Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99:3505–3516 source

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].”

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

In the paper

“Osteoclast precursors take up iron via Tfr1 and utilize six-transmembrane epithelial antigen of prostate (Steap4) as ferrireductase [262].”

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

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.”

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

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].”

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

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].”

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

In the paper

“These are best characterized in bacteria, but eukaryotes including fungi and mammals produce siderophores, too [16, 42, 67, 86, 106].”

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

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].”

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

In the paper

“At the cell surface membrane, macrophages possess the heme exporter Flvcr and its genetic deletion results in RPM iron overload [108].”

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

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].”

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

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].”

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

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].”

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

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.”

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

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].”

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

In the paper

“This suggests that EIM utilize Fpn1 to export iron and thus function as iron-rich nurse cells [259].”

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

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].”

What the sources say

• Not checked yetcites [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

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].”

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

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].”

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

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].”

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
• Not checked yetcites [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 source

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].”

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

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.”

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

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].”

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

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].”

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

In the paper

“Second, iron alters gene transcription, translation, and mitochondrial respiration in macrophages [165, 175].”

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

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.”

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].”

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

In the paper

“These effects may contribute to the inflammatory characteristics of sickle cell disease and can be ameliorated by the heme scavenger HPX.”

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].”

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

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].”

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

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].”

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

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.”

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.”