Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Arezes, João; Jung, Grace; Gabayan, Victoria; Valore, Erika V.; Ruchala, Piotr; Gulig, Paul A.; Ganz, Tomas; Nemeth, Elizabeta; Bulut, Yasemin

doi:10.1016/j.chom.2014.12.001

Cited by 202 publications

(194 citation statements)

References 47 publications

(55 reference statements)

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“…In contrast, the mRNA levels of hepcidin, a peptide hormone that regulates iron levels by degrading FPN, shows only moderate elevation at 24 h postinfection. Previous studies with infection models have shown hepcidin induction occurring during the first 12 h of infection (64), and the moderate change we observe is after the time window at which the hepcidin transcripts increase. The notable decrease in FPN mRNA suggests that hepatic iron regulation at this time point may also involve additional hepcidin-independent pathways that involve transcriptional regulation of FPN (65,66).…”

Section: Icl-1 Visualizes Changes In Labile Iron Pools In An a Baumasupporting

confidence: 56%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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Section: Icl-1 Visualizes Changes In Labile Iron Pools In An a Baumasupporting

confidence: 56%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

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“…19,20 Future investigations should also consider whether interindividual differences in hepcidin could manifest in differential susceptibility to other iron-requiring pathogens, such as Vibrio spp. 48 and HIV-1, or macrophagetropic pathogens, such as Mycobacterium tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study

Brickley

Spottiswoode

Kabyemela

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Abstract. Hepcidin, the master regulator of bioavailable iron, is a key mediator of anemia and also plays a central role in host defense against infection. We hypothesized that measuring hepcidin levels in cord blood could provide an early indication of interindividual differences in iron regulation with quantifiable implications for anemia, malaria, and mortality-related risk. Hepcidin concentrations were measured in cord plasma from a birth cohort (N = 710), which was followed for up to 4 years in a region of perennial malaria transmission in Muheza, Tanzania (2002Tanzania ( -2006. At the time of delivery, cord hepcidin levels were correlated with inflammatory mediators, iron markers, and maternal health conditions. Hepcidin levels were 30% (95% confidence interval [CI]: 12%, 44%) lower in children born to anemic mothers and 48% (95% CI: 11%, 97%) higher in placental malaria-exposed children. Relative to children in the lowest third, children in the highest third of cord hepcidin had on average 2.5 g/L (95% CI: 0.1, 4.8) lower hemoglobin levels over the duration of follow-up, increased risk of anemia and severe anemia (adjusted hazard ratio [HR]

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“…Mice lacking hepcidin show markedly decreased survival when infected with the siderophilic Vibrio vulnificus, and treatment with synthetic minihepcidins dramatically improves survival (54). The main mediator of increased hepcidin production during infection is IL-6 (55), which transcriptionally stimulates hepcidin synthesis via STAT3.…”

Section: Hepcidin a Component Of Innate Immunitymentioning

confidence: 99%

Iron homeostasis: An anthropocentric perspective

Coffey

Ganz

2017

Journal of Biological Chemistry

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159

167

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The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation.

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Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Cited by 202 publications

References 47 publications

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study

Iron homeostasis: An anthropocentric perspective

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