Iron homeostasis in host defence and inflammation

In the paper

“Susceptibility to death from infection with V. vulnificus correlated with the presence of non-transferrin-bound iron in the mouse sera and with the ability of sera from these mice to support rapid in vitro growth of V. vulnificus.”

What the sources say

• Not checked yetcites [52] Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015). This study shows that hepcidin-deficient mice are rapidly killed by V. vulnificus , but mice can be saved by the administration of minihepcidin, demonstrating the protective effect of hypoferraemia. source

In the paper

“Infection and inflammation induce hepcidin production, driving a decrease in plasma iron concentrations by inhibiting the absorption of iron and promoting the sequestration of iron in macrophages.”

What the sources say

• Not checked yetcites [26] Nicolas, G. et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110, 1037–1044 (2002). source
• Not checked yetcites [27] Goodnough, L. T., Nemeth, E. & Ganz, T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 116, 4754–4761 (2010). source

In the paper

“Lactic acid bacteria (also known as Lactobacillales) are normal components of the intestinal flora and have little or no requirement for iron; they thrive in the relatively iron-poor environment of the human intestine, but they may be displaced by other microorganisms when iron is administered60.”

What the sources say

• Not checked yetcites [60] Bailey, J. R., Probert, C. S. & Cogan, T. A. Identification and characterisation of an iron-responsive candidate probiotic. PLoS ONE 6, e26507 (2011). source

In the paper

“However, the local and systemic responses to aseptic inflammation in vivo are preserved in the absence of either of the two IREBPs3, which suggests that the role of the IREBPs in host defence and inflammation is minor or that the two IREBPs have mostly overlapping functions, an issue that needs to be examined further.”

What the sources say

• Not checked yetcites [3] Viatte, L., Grone, H. J., Hentze, M. W. & Galy, B. In vivo role(s) of the iron regulatory proteins (IRP) 1 and 2 in aseptic local inflammation. J. Mol. Med. 87, 913–921 (2009). source

In the paper

“Moreover, non-transferrin-bound iron can amplify tissue injury either because it catalyses the extracellular production of injurious reactive oxygen species (ROS) or because it is rapidly taken up some cell types, causing cellular iron overload with the secondary generation of ROS.”

In the paper

“This mechanism may function to prevent superinfection by additional malaria parasites during subsequent exposures to malaria-bearing mosquitoes, and it provides a form of innate immune protection in infants and children who have not yet developed an adaptive immune response to malarial parasites31.”

What the sources say

• Not checked yetcites [31] Portugal, S. et al. Host-mediated regulation of superinfection in malaria. Nat. Med. 17, 732–737 (2011). In pre-immune children, malaria parasitaemia induces hepcidin expression and redistributes iron from hepatocytes to macrophages, thereby interfering with the hepatic stage of superinfection by another malarial strain. source

In the paper

“Tissue iron overload and resulting toxicity is proportional to the severity and duration of hepcidin deficiency, and results in progressive iron-mediated damage to the liver, endocrine glands and cardiac myocytes.”

In the paper

“Interestingly, although most bacterial and some viral infections (such as influenza virus and HIV) rapidly increase hepcidin production in humans and mouse models, hepatitis B and hepatitis C virus infections fail to elicit systemic inflammatory responses and hepcidin production30.”

What the sources say

• Not checked yetcites [30] Armitage, A. E. et al. Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections. Proc. Natl Acad. Sci. USA 111, 12187–12192 (2014). This study shows that not all infections induce hepcidin: no induction of hepcidin or hypoferraemia was observed during the viraemic phase of hepatitis B or hepatitis C virus infection. source

In the paper

“The role of hepcidin as the iron-regulatory hormone that acts on ferroportin to modulate iron absorption and systemic iron distribution is now well accepted, but the strong connection between hepcidin and host defence is less well appreciated.”

In the paper

“Iron depletion of macrophages could therefore mimic the effects of hypoxia, stabilizing HIF1α and promoting the transcription and synthesis of IL-1β68 and perhaps other cytokines.”

What the sources say

• Not checked yetcites [68] Peyssonnaux, C. et al. Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178, 7516–7519 (2007). source

In the paper

“Malaria infection causes inflammation and increases hepcidin levels, redistributing iron to macrophages and, in the long term, away from hepatocytes that normally support the initial stage of infection.”

In the paper

“Also similar to defensins, hepcidin has direct antimicrobial activity in vitro, but the concentrations and conditions required for this activity seem to be outside of the physiological range.”

In the paper

“In ex vivo erythrocytes from iron-deficient donors, the malarial parasite Plasmodium falciparum invades fewer cells and shows slower intracellular growth than in erythrocytes from iron-replete donors66.”

What the sources say

• Not checked yetcites [66] Clark, M. A. et al. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat. Commun. 5, 4446 (2014). source

In the paper

“IL-1β mediates systemic inflammation and activates important host defence mechanisms69.”

What the sources say

• Not checked yetcites [69] Horino, T. et al. Interleukin-1-deficient mice exhibit high sensitivity to gut-derived sepsis caused by Pseudomonas aeruginosa. Cytokine 30, 339–346 (2005). source

In the paper

“Indeed, a recent study showed that exogenous hepcidin is protective against renal ischaemia–reperfusion injury and oxidative stress, and that hepcidin deficiency exacerbates these forms of injury32.”

What the sources say

• Not checked yetcites [32] Scindia, Y. et al. Hepcidin mitigates renal ischemia–reperfusion injury by modulating systemic iron homeostasis. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2014101037 (2015). source

In the paper

“Motivated to understand the connection between iron supplementation and diarrhoeal illness in African children, some but not all studies found an altered composition of the intestinal flora and increased inflammation in children who were treated to prevent or reverse iron deficiency61–63.”

What the sources say

• Not checked yetcites [61] Zimmermann, M. B. et al. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am. J. Clin. Nutr. 92, 1406–1415 (2010). source
• Not checked yetcites [62] Jaeggi, T. et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 64, 731–742 (2015). source
• Not checked yetcites [63] Dostal, A. et al. Effects of iron supplementation on dominant bacterial groups in the gut, faecal SCFA and gut inflammation: a randomised, placebo-controlled intervention trial in South African children. Br. J. Nutr. 112, 547–556 (2014). source

In the paper

“Another set of regulatory factors conveys the iron requirements for erythropoiesis and includes the recently identified hormone erythroferrone12, which is produced by erythroblasts in response to erythropoietic stimulation by endogenous or synthetic erythropoietin. Erythroferrone suppresses hepcidin synthesis, making more iron available for enhanced erythropoiesis.”

What the sources say

• Not checked yetcites [12] Kautz, L. et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678–684 (2014). source

In the paper

“Although the induction of IL-1β is not primarily modulated by hepcidin, hepcidin causes iron sequestration in macrophages (FIG. 3) and would be expected to have an anti-inflammatory effect67.”

What the sources say

• Not checked yetcites [67] Pagani, A. et al. Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood 118, 736–746 (2011). source

In the paper

“Cellular iron overload increases the production of ROS, causing cellular injury.”

In the paper

“Paradoxically, studies in mouse models have shown that infections with intracellular microorganisms that reside in macrophages may be enhanced by hepcidin-induced iron sequestration, and conversely, hepcidin deficiency in mouse models of hereditary haemochromatosis may inhibit the growth of macrophage-resident bacteria, including Mycobacteria tuberculosis53 or Salmonella enterica serovar enterica”

What the sources say

• Not checked yetcites [53] Olakanmi, O., Schlesinger, L. S. & Britigan, B. E. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J. Leukoc. Biol. 81, 195–204 (2007). source
• Not checked yetcites [54] Nairz, M. et al. Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2. Blood 114, 3642–3651 (2009). References 53 and 54 raise the possibility that hepcidin deficiency, while promoting certain extracellular infections, may be protective against intracellular pathogens. source

In the paper

“Mice engineered to lack hepcidin fail to develop hypoferraemia after inflammatory stimulation, their serum iron concentrations may even increase during infection or inflammation, and their anaemia of inflammation is milder28,29.”

What the sources say

• Not checked yetcites [28] Kim, A. et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 123, 1129–1136 (2014). source
• Not checked yetcites [29] Gardenghi, S. et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 123, 1137–1145 (2014). References 28 and 29 show that IL-6 and hepcidin are important but not exclusive mediators of anaemia of inflammation in a mouse model of severe anaemia induced by heat-killed bacteria. source

In the paper

“Anaemia owing to ineffective erythropoiesis, as occurs most prominently in patients with β-thalassaemia, is associated with severe iron overload that develops even in the absence of blood transfusions but is exacerbated in patients who receive repeated transfusions36,37.”

What the sources say

• Not checked yetcites [36] Musallam, K. M., Cappellini, M. D. & Taher, A. T. Iron overload in β-thalassemia intermedia: an emerging concern. Curr. Opin. Hematol. 20, 187–192 (2013). source
• Not checked yetcites [37] Maggio, A. et al. Iron chelation therapy in thalassemia major: a systematic review with meta-analyses of 1520 patients included on randomized clinical trials. Blood Cells Mol. Dis. 47, 166–175 (2011). source

In the paper

“most studies suggest that NRAMP1 transports iron from phagosomes and other vacuoles that contain microorganisms to the cytoplasm of macrophages76–78, thereby starving vacuolar microorganisms of iron.”

What the sources say

• Not checked yetcites [76] Soe-Lin, S. et al. Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc. Natl Acad. Sci. USA 106, 5960–5965 (2009). source
• Not checked yetcites [77] Cellier, M. F., Courville, P. & Campion, C. Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect. 9, 1662–1670 (2007). source
• Not checked yetcites [78] Forbes, J. R. & Gros, P. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102, 1884–1892 (2003). source

In the paper

“S. Typhimurium elicits this response by a mechanism that is dependent on IL-6 and oestrogen-related receptor-γ (ESRRγ)88.”

What the sources say

• Not checked yetcites [88] Kim, D. K. et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat. Med. 20, 419–424 (2014). source

In the paper

“In this way, these macrophages provide the bacteria with a source of iron from erythrophagocytosis and an M2 macrophage environment with attenuated antimicrobial mechanisms favouring the survival of the bacteria.”

In the paper

“NRAMP1 expression is also stimulated by IFNγ72, and NRAMP1-mediated iron export from phagosomes containing intracellular microorganisms may help to counter the effect of systemic hepcidin.”

What the sources say

• Not checked yetcites [72] Canonne-Hergaux, F., Gruenheid, S., Govoni, G. & Gros, P. The Nramp1 protein and its role in resistance to infection and macrophage function. Proc. Assoc. Am. Physicians 111, 283–289 (1999). source

In the paper

“An effective iron chelator must be nontoxic, must have higher affinity for ferric iron than bacterial siderophores and must not be recognized by microbial siderophore transporters94.”

What the sources say

• Not checked yetcites [94] Zhou, T., Ma, Y., Kong, X. & Hider, R. C. Design of iron chelators with therapeutic application. Dalton Trans. 41, 6371–6389 (2012). source

In the paper

“Iron deficiency is widespread in developing countries and is a major cause of chronic illness and loss of economic productivity56.”

What the sources say

• Not checked yetcites [56] Pasricha, S. R., Drakesmith, H., Black, J., Hipgrave, D. & Biggs, B. A. Control of iron deficiency anemia in low- and middle-income countries. Blood 121, 2607–2617 (2013). source

In the paper

“The uptake of transferrin by Neisseria species is specific to hominid transferrin, indicating that this specialized uptake mechanism facilitates their residence in the human host and several other hominids83.”

What the sources say

• Not checked yetcites [83] Noinaj, N. et al. Structural basis for iron piracy by pathogenic Neisseria. Nature 483, 53–58 (2012). source

In the paper

“Nevertheless, these mice develop hypoferraemia, indicating that the nitric oxide-dependent mechanism operates at a local level and requires the presence of bacteria within the macrophage, leaving most iron-recycling macrophages under the dominant regulatory influence of hepcidin.”

In the paper

“In this model, mini-hepcidins rapidly decreased iron concentrations in the plasma and extracellular fluid, and thereby decreased the concentrations of non-transferrin-bound iron, which is a likely source of iron for siderophilic bacteria.”

What the sources say

• Not checked yetcites [52] Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015). This study shows that hepcidin-deficient mice are rapidly killed by V. vulnificus , but mice can be saved by the administration of minihepcidin, demonstrating the protective effect of hypoferraemia. source

In the paper

“In chronic infection with S. Typhimurium, the bacteria may induce erythrophagocytosis and the conversion of hepatic and splenic macrophages into an M2 phenotype, a process that also requires host signals but has not been characterized in molecular detail93.”

What the sources say

• Not checked yetcites [93] Pilonieta, M. C., Moreland, S. M., English, C. N. & Detweiler, C. S. Salmonella enterica infection stimulates macrophages to hemophagocytose. mBio 5, e02211 (2014). source

In the paper

“Although the hepcidin–ferroportin system seems to function maladaptively during infections with intracellular microorganisms, this host response could be mitigated in infected macrophages by local mechanisms that counteract the systemic effects of hepcidin.”

In the paper

“IL-6 is increased early in most microbial infections and it stimulates hepcidin transcription via the JAK2–STAT3 pathway in a manner dependent on STAT3-binding motifs in the promoter of HAMP (the hepcidin gene)89–91.”

What the sources say

• Not checked yetcites [89] Wrighting, D. M. & Andrews, N. C. Interleukin-6 induces hepcidin expression through STAT3. Blood 108, 3204–3209 (2006). source
• Not checked yetcites [90] Fleming, R. E. Hepcidin activation during inflammation: make it STAT. Gastroenterology 132, 447–449 (2007). source
• Not checked yetcites [91] Pietrangelo, A. et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132, 294–300 (2007). source

In the paper

“Despite several decades of research in this area that have yielded three successful drugs for the treatment of iron overload disorders, and evidence of in vitro microbistatic activity for several compounds95, no chelator has yet been adopted as an antimicrobial therapeutic.”

What the sources say

• Not checked yetcites [95] Thompson, M. G., Corey, B. W., Si, Y., Craft, D. W. & Zurawski, D. V. Antibacterial activities of iron chelators against common nosocomial pathogens. Antimicrob. Agents Chemother. 56, 5419–5421 (2012). source

In the paper

“A direct hepcidin-mediated anti-inflammatory effect mediated by ferroportin and the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway was proposed70, but JAK–STAT-mediated signalling by ferroportin was not confirmed in subsequent more-detailed studies71.”

What the sources say

• Not checked yetcites [70] De Domenico, I. et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J. Clin. Invest. 120, 2395–2405 (2010). source
• Not checked yetcites [71] Ross, S. L. et al. Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT. Cell Metab. 15, 905–917 (2012). source

In the paper

“Chemical inhibition of the ESRRγ pathway in a mouse model significantly decreased bacterial burden and modestly improved the survival of infected mice88.”

What the sources say

• Not checked yetcites [88] Kim, D. K. et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat. Med. 20, 419–424 (2014). source

In the paper

“Finally, the exquisite dependence of most microorganisms on iron provides a rationale for the design of new antimicrobials that target iron uptake mechanisms in pathogenic microorganisms.”