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

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].”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

In the paper

“Two elegant studies have shown that the application of nanoparticles to tumor-bearing mice is sufficient to induce clinical remission.”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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].”

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

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].”

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

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).”

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.”

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

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].”

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

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].”

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

In the paper

“The liver acts as central orchestrator of iron metabolism through various mechanisms.”

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].”

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

In the paper

“Although many genes involved in heme iron recycling are thus HIF-inducible, HIF-1α and HIF-2α in macrophages are dispensable for heme iron recycling under hemolytic stress [147].”

What the sources say

• Not checked yetcites [147] Mathieu JR, Heinis M, Zumerle S, Delga S, Le Bon A, Peyssonnaux C (2014) Investigating the real role of HIF-1 and HIF-2 in iron recycling by macrophages. Haematologica 99:e112–e114 source

In the paper

“A central role of this multifunctional system beyond immunity and tissue repair is to control the body’s metabolic needs for iron.”

In the paper

“In steady-state conditions, RBC recycling mainly takes place in the spleen [48, 213].”

What the sources say

• Not checked yetcites [48] Delaby C, Pilard N, Hetet G, Driss F, Grandchamp B, Beaumont C, Canonne-Hergaux F (2005) A physiological model to study iron recycling in macrophages. Exp Cell Res 310:43–53 source
• 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

In the paper

“To compensate, blood-derived monocytes fill the partial niche after KC loss and differentiate into a transient macrophage population that has a unique phenotype including the high expression of the CC-chemokine receptor 2 (CCR2) [231].”

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

In the paper

“Rising heme levels induce Bach1 proteosomal degradation, releasing the brake on two types of down-stream pathways. First, the competitive inhibition of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) binding to antioxidant-response elements (ARE) ceases for genes containing AREs [51, 145, 221], such as ferritin h chain (FTH), FPN1, heme-regulated gene-1 (HRG1), and heme oxygenase (Hmox1) [102,”

What the sources say

• Not checked yetcites [51] Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal AK (2005) Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 280:16891–16900 source
• Not checked yetcites [145] Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, Muckenthaler MU (2010) Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica 95:1261–1268 source
• Not checked yetcites [221] Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo MM, Yamamoto M, Igarashi K (2002) Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 21:5216–5224 source
• Not checked yetcites [102] Iwasaki K, Mackenzie EL, Hailemariam K, Sakamoto K, Tsuji Y (2006) Hemin-mediated regulation of an antioxidant-responsive element of the human ferritin H gene and role of Ref-1 during erythroid differentiation of K562 cells. Mol Cell Biol 26:2845–2856 source
• Not checked yetcites [190] Pietsch EC, Chan JY, Torti FM, Torti SV (2003) Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. J Biol Chem 278:2361–2369 source

In the paper

“Macrophages infiltrating the injured skeletal muscle induce the expression of Hmox1, CD163, and FT to contain and detoxify heme [41].”

What the sources say

• Not checked yetcites [41] Corna G, Caserta I, Monno A, Apostoli P, Manfredi AA, Camaschella C, Rovere-Querini P (2016) The repair of skeletal muscle requires iron recycling through macrophage ferroportin. J Immunol 197:1914–1925 source

In the paper

“For instance, surplus iron in thalassemic patients may promote osteoclast differentiation and function and thus contribute to bone resorption [101].”

What the sources say

• Not checked yetcites [101] Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M, Shimohata N, Aburatani H, Taketani S, Lelliott CJ, Vidal-Puig A, Ikeda K (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 15:259–266 source

In the paper

“In summary, hepatocytes, KC, and endothelial cells cooperate to maintain the body’s iron homeostasis and we are beginning to decipher the signals that coordinate the function of these and other liver-resident cell types.”

In the paper

“In addition, the transcription factor peroxisome proliferator-activated receptor-gamma coactivator 1 beta (PGC-1ß) is essential for osteoclast differentiation [101].”

What the sources say

• Not checked yetcites [101] Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M, Shimohata N, Aburatani H, Taketani S, Lelliott CJ, Vidal-Puig A, Ikeda K (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 15:259–266 source

In the paper

“These effects along with oxidative stress to photoreceptors can be prevented by the oral iron chelator DFP [217].”

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

“Indeed, long-term induction of Hmox1 promotes the resolution of ICH [260].”

What the sources say

• Not checked yetcites [260] Zhang Z, Song Y, Li D, Zhu H, Liang R, Gu Y, Pang Y, Qi J, Wu H, Wang J (2017) Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice. J Cereb Blood Flow Metab 37:25–38 source

In the paper

“Elevated vascular cell adhesion molecule 1 (VCAM1) levels are an accurate biomarker to diagnose this condition, but whether the adhesion molecule is also involved in its pathogenesis remains unclear [170].”

What the sources say

• Not checked yetcites [170] Nell-Duxneuner V, Axmann R, Husar-Memmer E, Dallos T, Datz C, Stadlmayr A, Aigner E, Englbrecht M, Schett G, Zwerina J (2013) VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis. Ann Rheum Dis 72:2006–2010 source

In the paper

“Apart from neurons, activated microglia can accumulate iron in Alzheimer’s disease, e.g., in the hippocampus as detected my ultra-high-resolution MR [258].”

What the sources say

• Not checked yetcites [258] Zeineh MM, Chen Y, Kitzler HH, Hammond R, Vogel H, Rutt BK (2015) Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol Aging 36:2483–2500 source

In the paper

“These findings thus contrast to what has been shown for co-cultured primary Kupffer cells and hepatocytes inasmuch as culture supernatants from primary Kupffer cells blunted hepcidin production [228].”

What the sources say

• Not checked yetcites [228] Theurl M, Theurl I, Hochegger K, Obrist P, Subramaniam N, van Rooijen N, Schuemann K, Weiss G (2008b) Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression. J Mol Med (Berl) 86:825–835 source

In the paper

“Therefore, early DFO treatment in experimental ICH translates into improved neurologic outcome [222].”

What the sources say

• Not checked yetcites [222] Sun YM, Wang YT, Jiang L, Xue MZ (2016) The effects of deferoxamine on inhibition for microglia activation and protection of secondary nerve injury after intracerebral hemorrhage in rats. Pak J Pharm Sci 29:1087–1093

In the paper

“For instance, in neuronal cells exposed to amyloid beta peptide fragments, iron chelation with DFO or deferiprone (DFP) reduces ROS generation via the NADPH oxidase [181].”

What the sources say

• Not checked yetcites [181] Part K, Kunnis-Beres K, Poska H, Land T, Shimmo R, Zetterstrom Fernaeus S (2015) Amyloid beta25-35 induced ROS-burst through NADPH oxidase is sensitive to iron chelation in microglial Bv2 cells. Brain Res 1629:282–290 source

In the paper

“A mechanism comparable to hemolysis-induced RBC recycling in the liver has recently been described in the skeletal muscle in the context of rhabdomyolysis.”

In the paper

“Mice with the homologous mutation in Hfe have increased FTL chain expression in microglia, suggesting iron overload [169].”

What the sources say

• Not checked yetcites [169] Nandar W, Neely EB, Unger E, Connor JR (2013) A mutation in the HFE gene is associated with altered brain iron profiles and increased oxidative stress in mice. Biochim Biophys Acta 1832:729–741 source

In the paper

“Apparently, both Tfr1-mediated iron uptake and PGC-1ß activation ensure mitochondrial respiration in osteoclasts as prerequisite for energy generation and proton secretion.”

In the paper

“In addition, mutated FTL proteins may have a dominant negative effect on FT’s stability and resistance to oxidative damage [12, 140, 160].”

What the sources say

• Not checked yetcites [12] Baraibar MA, Barbeito AG, Muhoberac BB, Vidal R (2012) A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage. Free Radic Biol Med 52:1692–1697 source
• Not checked yetcites [140] Luscieti S, Santambrogio P, Langlois d'Estaintot B, Granier T, Cozzi A, Poli M, Gallois B, Finazzi D, Cattaneo A, Levi S, Arosio P (2010) Mutant ferritin L-chains that cause neurodegeneration act in a dominant-negative manner to reduce ferritin iron incorporation. J Biol Chem 285:11948–11957 source
• Not checked yetcites [160] Muhoberac BB, Baraibar MA, Vidal R (2013) Iron loading-induced aggregation and reduction of iron incorporation in heteropolymeric ferritin containing a mutant light chain that causes neurodegeneration. Biochim Biophys Acta 1812:544–548 source

In the paper

“This suggests that endothelial Fpn1 is the gatekeeper for iron transport into the retina [232].”

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

“However, it is well documented that arterial macrophages, typically identified by CD68 histochemistry on histologic sections within atherosclerotic lesions, contain larger amounts of FT than those outside plaques [129, 256].”

What the sources say

• Not checked yetcites [129] Li W, Xu LH, Forssell C, Sullivan JL, Yuan XM (2008) Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques. Exp Biol Med (Maywood) 233:818–826 source
• Not checked yetcites [256] Yuan XM (1999) Apoptotic macrophage-derived foam cells of human atheromas are rich in iron and ferritin, suggesting iron-catalysed reactions to be involved in apoptosis. Free Radic Res 30:221–231 source

In the paper

“Local iron accumulation in the brain (particularly in neurons and astrocytes) is linked to several neurodegenerative disorders, collectively referred to as neurodegeneration with brain iron accumulation (NBIA) [127].”

What the sources say

• Not checked yetcites [127] Levi S, Finazzi D (2014) Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms. Front Pharmacol 5:99 source

In the paper

“Although hepcidin production has been observed in the brain, co-culture models suggest that microglia enhance hepcidin expression by neurons via IL-6 in a paracrine fashion [191].”

What the sources say

• Not checked yetcites [191] Qian ZM, He X, Liang T, Wu KC, Yan YC, Lu LN, Yang G, Luo QQ, Yung WH, Ke Y (2014) Lipopolysaccharides upregulate hepcidin in neuron via microglia and the IL-6/STAT3 signaling pathway. Mol Neurobiol 50:811–820 source

In the paper

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

In the paper

“In conclusion, evidence is accumulating for a cross-talk between the regulators of iron and cholesterol metabolism both systemically and locally in the microenvironment of the atherosclerotic plaque.”

In the paper

“One such mechanism to maintain cytosolic iron levels are the iron regulatory proteins (IRPs) 1 and 2 [5, 179, 195].”

What the sources say

• Not checked yetcites [5] Anderson CP, Shen M, Eisenstein RS, Leibold EA (2012) Mammalian iron metabolism and its control by iron regulatory proteins. Biochim Biophys Acta 1823:1468–1483 source
• Not checked yetcites [179] Pantopoulos K, Weiss G, Hentze MW (1996) Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 16:3781–3788 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

“Data in support of this concept has been generated using the CD169-DTR model: The depletion of EIM (and other CD169+ macrophages) had only little impact on the restoration of erythropoiesis after BM transplantation.”

What the sources say

• Not checked yetcites [38] Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas D, Kunisaki Y, Pinho S, Leboeuf M, Noizat C, van Rooijen N, Tanaka M, Zhao ZJ, Bergman A, Merad M, Frenette PS (2013) CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med 19:429–436 source

In the paper

“Therefore, macrophage IRPs are required to regulate their effector functions upon infection with an iron-dependent pathogen.”

In the paper

“Lcn2 binds distinct types of so-called siderophores, low molecular mass compounds with remarkably high affinity and specificity for ferric iron.”

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 [70] Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921 source

In the paper

“IRPs sense free labile iron and control cellular iron homeostasis at the post-transcriptional level: Due to their ability to interact with iron-responsive elements (IREs) that are present in the non-coding mRNA sequences of Tfr1, Dmt1, Fpn1, FTH, and FTL chains, fluctuations in intracellular iron are promptly counterbalanced [179, 195].”

What the sources say

• Not checked yetcites [179] Pantopoulos K, Weiss G, Hentze MW (1996) Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 16:3781–3788 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

“Concretely, a moderate decrease of iron supply to erythroblasts as deduced from the reduced Hb content in reticulocytes was observed [38].”

What the sources say

• Not checked yetcites [38] Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas D, Kunisaki Y, Pinho S, Leboeuf M, Noizat C, van Rooijen N, Tanaka M, Zhao ZJ, Bergman A, Merad M, Frenette PS (2013) CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med 19:429–436 source

In the paper

“Erythroid island macrophages (EIM) are a population of BM-resident macrophages that support erythropoiesis as “nurse cells” [17, 192].”

What the sources say

• Not checked yetcites [17] Bessis M, Breton-Gorius J (1959) New observations on the erythroblast islet and rhopheocytosis of ferritin. Rev Hematol 14:165–197
• Not checked yetcites [192] Ramos P, Casu C, Gardenghi S, Breda L, Crielaard BJ, Guy E, Marongiu MF, Gupta R, Levine RL, Abdel-Wahab O, Ebert BL, Van Rooijen N, Ghaffari S, Grady RW, Giardina PJ, Rivella S (2013) Macrophages support pathological erythropoiesis in polycythemia vera and beta-thalassemia. Nat Med 19:437–445 source

In the paper

“Macrophage iron metabolism and immune functions are interconnected [57, 79, 165, 247].”

What the sources say

• Not checked yetcites [57] Drakesmith H, Prentice AM (2012) Hepcidin and the iron-infection axis. Science 338:768–772 source
• Not checked yetcites [79] Ganz T, Nemeth E (2015) Iron homeostasis in host defence and inflammation. Nat Rev Immunol 15:500–510 source
• 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 [247] Weiss G, Schaible UE (2015) Macrophage defense mechanisms against intracellular bacteria. Immunol Rev 264:182–203 source

In the paper

“Therefore, due to its sensitivity to both oxygen and iron, the transcription factor HIF-1α appears to hold a central position in the interplay of macrophage iron homeostasis and immunity.”

In the paper

“Moreover, hypoxia impairs NO production by Nos2 and thus blunts the antimicrobial activity of macrophages towards Leishmania major [142].”

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

In the paper

“One of these papers implicated a direct tumoricidal effect of iron delivered by ultrasmall polyethylene glycol particles and attributed tumor regression to the induction of ferroptosis in malignant cells [112].”

What the sources say

• Not checked yetcites [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 source

In the paper

“In addition, IFN-γ in conjunction with TLR4 ligation results in NF-κB-dependent activation of HIF-1α and increased transcription of TfR1 thus aggravating macrophage iron overload [224].”

What the sources say

• Not checked yetcites [224] Tacchini L, Gammella E, De Ponti C, Recalcati S, Cairo G (2008) Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. J Biol Chem 283:20674–20686 source

In the paper

“Accordingly, free heme, which is predicted to accumulate when Hmox1 is inhibited, activates NF-κB to induce TNF and Nos2 transcription resulting in improved control of Salmonella infection [154].”

What the sources say

• Not checked yetcites [154] Mitterstiller AM, Haschka D, Dichtl S, Nairz M, Demetz E, Talasz H, Soares MP, Einwallner E, Esterbauer H, Fang FC, Geley S, Weiss G (2016) Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella typhimurium infection. Cell Microbiol 18:1374–1389 source

In the paper

“Intriguingly, the accumulation of heme during the course of sepsis-induced hemolysis also impairs phagocyte functions due to interference with actin cytoskeleton rearrangements resulting in poor outcome [146].”

What the sources say

• Not checked yetcites [146] Martins R, Maier J, Gorki AD, Huber KV, Sharif O, Starkl P, Saluzzo S, Quattrone F, Gawish R, Lakovits K, Aichinger MC, Radic-Sarikas B, Lardeau CH, Hladik A, Korosec A, Brown M, Vaahtomeri K, Duggan M, Kerjaschki D, Esterbauer H, Colinge J, Eisenbarth SC, Decker T, Bennett KL, Kubicek S, Sixt M, Superti-Furga G, Knapp S (2016) Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat Immunol source

In the paper

“First, a range of intracellular microbes can resist killing by macrophages by gaining access to macrophage iron pools [30, 245].”

What the sources say

• Not checked yetcites [30] Cassat JE, Skaar EP (2013) Iron in infection and immunity. Cell Host Microbe 13:509–519 source
• Not checked yetcites [245] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790:600–605 source

In the paper

“However, some data suggest that Nramp1 in fact pumps iron into the phagolysosome where it may boost ROS generation [121, 122].”

What the sources say

• Not checked yetcites [121] Kuhn DE, Baker BD, Lafuse WP, Zwilling BS (1999) Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169. J Leukoc Biol 66:113–119 source
• Not checked yetcites [122] Kuhn DE, Lafuse WP, Zwilling BS (2001) Iron transport into mycobacterium avium-containing phagosomes from an Nramp1(Gly169)-transfected RAW264.7 macrophage cell line. J Leukoc Biol 69:43–49 source

In the paper

“A phagolysosomal transporter with homology to Dmt1 (Nramp2) is Nramp1 [8, 20, 71, 75].”

What the sources say

• Not checked yetcites [8] Atkinson PG, Blackwell JM, Barton CH (1997) Nramp1 locus encodes a 65 kDa interferon-gamma-inducible protein in murine macrophages. Biochem J 325(Pt 3):779–786 source
• Not checked yetcites [20] Blackwell JM (1996) Structure and function of the natural-resistance-associated macrophage protein (Nramp1), a candidate protein for infectious and autoimmune disease susceptibility. Mol Med Today 2:205–211 source
• Not checked yetcites [71] Forbes JR, Gros P (2001) Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol 9:397–403 source
• Not checked yetcites [75] Fritsche G, Nairz M, Theurl I, Mair S, Bellmann-Weiler R, Barton HC, Weiss G (2007) Modulation of macrophage iron transport by Nramp1 (Slc11a1). Immunobiology 212:751–757 source

In the paper

“These novel and exciting data support the general idea that the modulation of macrophage iron homeostasis is a promising way to control their immune functions and alter myeloid-driven disease processes in infection, auto-immunity, atherosclerosis, and possibly also cancer [143, 167]”

What the sources say

• Not checked yetcites [143] Mair SM, Nairz M, Bellmann-Weiler R, Muehlbacher T, Schroll A, Theurl I, Moser PL, Talasz H, Fang FC, Weiss G (2011) Nifedipine affects the course of Salmonella enterica serovar Typhimurium infection by modulating macrophage iron homeostasis. J Infect Dis 204:685–694 source
• 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

In the paper

“Most studies have shown that Nramp1 shifts iron and other divalent cations from the phagolysosome to the cytosol.”

What the sources say

• Not checked yetcites [32] Cellier MF, Courville P, Campion C (2007) Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect 9:1662–1670 source
• Not checked yetcites [71] Forbes JR, Gros P (2001) Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol 9:397–403 source
• Not checked yetcites [225] Techau ME, Valdez-Taubas J, Popoff JF, Francis R, Seaman M, Blackwell JM (2007) Evolution of differences in transport function in Slc11a family members. J Biol Chem 282:35646–35656 source
• Not checked yetcites [249] Wessling-Resnick M (2015) Nramp1 and other transporters involved in metal withholding during infection. J Biol Chem 290:18984–18990 source

In the paper

“Its cation transport function is directly linked to the antimicrobial activity of macrophages and DCs [74, 163, 219].”

What the sources say

• Not checked yetcites [74] Fritsche G, Dlaska M, Barton H, Theurl I, Garimorth K, Weiss G (2003) Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression. J Immunol 171:1994–1998 source
• Not checked yetcites [163] Nairz M, Fritsche G, Crouch ML, Barton HC, Fang FC, Weiss G (2009) Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition. Cell Microbiol 11:1365–1381 source
• Not checked yetcites [219] Stober CB, Brode S, White JK, Popoff JF, Blackwell JM (2007) Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function. Infect Immun 75:5059–5067 source

In the paper

“In this context, iron present in heme can stimulate the production of ROS and of pro-inflammatory cytokines such as TNF, IL-1ß, and IL-6 [241].”

What the sources say

• Not checked yetcites [241] Vinchi F, Costa da Silva M, Ingoglia G, Petrillo S, Brinkman N, Zuercher A, Cerwenka A, Tolosano E, Muckenthaler MU (2016) Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127:473–486 source

In the paper

“In contrast, arginase-1, which depletes the Nos2 substrate arginine by converting it to ornithine [62, 205], is reduced by heme.”

What the sources say

• Not checked yetcites [62] El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, Konig T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ (2008) Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9:1399–1406 source
• Not checked yetcites [205] Schleicher U, Paduch K, Debus A, Obermeyer S, Konig T, Kling JC, Ribechini E, Dudziak D, Mougiakakos D, Murray PJ, Ostuni R, Korner H, Bogdan C (2016) TNF-mediated restriction of arginase 1 expression in myeloid cells triggers type 2 NO synthase activity at the site of infection. Cell Rep 15:1062–1075 source

In the paper

“Specifically, macrophage functions driven by IFN-γ are impaired when macrophages are exposed to surplus iron [138, 162, 176] largely because iron directly inhibits the binding activities of the transcription factors nuclear factor interleukin-6 (NF-IL6) and hypoxia-inducible factor (HIF)-1α [55, 153] [176].”

What the sources say

• 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
• Not checked yetcites [162] Nairz M, Fritsche G, Brunner P, Talasz H, Hantke K, Weiss G (2008) Interferon-gamma limits the availability of iron for intramacrophage Salmonella typhimurium. Eur J Immunol 38:1923–1936 source
• Not checked yetcites [176] Oexle H, Kaser A, Most J, Bellmann-Weiler R, Werner ER, Werner-Felmayer G, Weiss G (2003) Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells. J Leukoc Biol 74:287–294 source
• Not checked yetcites [55] Dlaska M, Weiss G (1999) Central role of transcription factor NF-IL6 for cytokine and iron-mediated regulation of murine inducible nitric oxide synthase expression. J Immunol 162:6171–6177 source
• Not checked yetcites [153] Melillo G, Taylor LS, Brooks A, Musso T, Cox GW, Varesio L (1997) Functional requirement of the hypoxia-responsive element in the activation of the inducible nitric oxide synthase promoter by the iron chelator desferrioxamine. J Biol Chem 272:12236–12243 source

In the paper

“Although intended to be otherwise inert, it has recently been uncovered in tumor models that nanoparticles may alter the biology of both tumor cells and tumor-associated macrophages, albeit with favorable results.”

In the paper

“Because of its inhibitory effects on NF-IL6 and HIF-1α, iron excess blocks Nos2 transcription and the high output formation of NO which worsens bacterial killing of iron-laden macrophages [91, 164].”

What the sources say

• Not checked yetcites [91] Haschka D, Nairz M, Demetz E, Wienerroither S, Decker T, Weiss G (2015) Contrasting regulation of macrophage iron homeostasis in response to infection with Listeria monocytogenes depending on localization of bacteria. Metallomics 7:1036–1045 source
• Not checked yetcites [164] Nairz M, Schleicher U, Schroll A, Sonnweber T, Theurl I, Ludwiczek S, Talasz H, Brandacher G, Moser PL, Muckenthaler MU, Fang FC, Bogdan C, Weiss G (2013) Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. J Exp Med 210:855–873 source

In the paper

“Clinical data as well as many studies in infection models show that macrophage iron overload, often resulting from hemolysis or iron supplementation, interferes with their antimicrobial activity (Fig. 2b).”

In the paper

“One of macrophages’ central metabolic functions is to eliminate senescent and damaged RBCs and to recycle their heme-bound iron to maintain systemic and cellular iron homeostasis.”

In the paper

“The role of macrophages in iron handling preserves iron homeostasis and tissue integrity.”