Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology

Abstract Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)–dependent and –independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-γ and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-γ and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-γ and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.

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A role for sex and a common HFE gene variant in brain iron uptake

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17701949 ◽

2017 ◽

Vol 38 (3) ◽

pp. 540-548 ◽

Cited By ~ 7

Author(s):

Kari A Duck ◽

Elizabeth B Neely ◽

Ian A Simpson ◽

James R Connor

Keyword(s):

Blood Brain Barrier ◽

Iron Uptake ◽

Iron Transport ◽

Iron Status ◽

Brain Barrier ◽

Hfe Gene ◽

Brain Iron ◽

Cellular Iron ◽

Blood Brain ◽

The Brain

HFE (high iron) is an essential protein for regulating iron transport into cells. Mutations of the HFE gene result in loss of this regulation causing accumulation of iron within the cell. The mutated protein has been found increasingly in numerous neurodegenerative disorders in which increased levels of iron in the brain are reported. Additionally, evidence that these mutations are associated with elevated brain iron challenges the paradigm that the brain is protected by the blood–brain barrier. While much has been studied regarding the role of HFE in cellular iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. We investigated regulation of iron transport into the brain using a mouse model with a mutation in the HFE gene. We demonstrated that the rate of radiolabeled iron (59Fe) uptake was similar between the two genotypes despite higher brain iron concentrations in the mutant. However, there were significant differences in iron uptake between males and females regardless of genotype. These data indicate that brain iron status is consistently maintained and tightly regulated at the level of the blood–brain barrier.

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Regulation of the Profile of Iron-Management Proteins in Brain Microvasculature

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000095800.98378.03 ◽

2004 ◽

Vol 24 (1) ◽

pp. 67-74 ◽

Cited By ~ 40

Author(s):

Joseph R. Burdo ◽

Ian A. Simpson ◽

Sharon Menzies ◽

John Beard ◽

James R. Connor

Keyword(s):

Iron Transport ◽

Iron Status ◽

Protein Profile ◽

Brain Iron ◽

Divalent Metal Transporter 1 ◽

Iron Storage ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

Brain Microvasculature ◽

The Brain

The distribution of brain iron is heterogeneous, but the mechanism by which these regional differences are achieved and maintained is unknown. In this study, the authors test two hypotheses related to brain iron transport. The first is that there is regional variability in the profile of proteins associated with iron transport and storage in the brain microvasculature. The second hypothesis is that the iron status of the brain will dictate the response of the protein profile in the microvasculature to changes in systemic iron status. The profile analysis consists of transferrin (iron transport), ferritin (iron storage), transferrin receptor (iron uptake), and divalent metal transporter 1 (release of iron from endosomes). An additional protein involved in cellular iron efflux, ferroportin, was not detected in brain microvasculature. The results show that there are significantly higher levels of these proteins in the microvasculature from each area of the brain compared to a whole brain homogenate, but no regional differences within the microvasculature. The levels of ferritin observed in the microvasculature indicate that the microvascular endothelial cells have significant iron storage capacity. There are no significant changes in the regional protein profiles in response to systemic iron manipulation when brain iron status was normal. In contrast, in Belgrade rats, whose brain is iron deficient, the expression of both divalent metal transporter 1 and transferrin receptor was increased compared with control in almost all brain regions examined, but not transferrin or ferritin. These findings indicate that regional brain iron heterogeneity is not maintained by differences in microvascular iron-management protein levels. The results also indicate that brain iron status dictates the response of the microvascular protein profile to systemic iron manipulation.

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The transcytosis of divalent metal transporter 1 and apo-transferrin during iron uptake in intestinal epithelium

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00005.2002 ◽

2002 ◽

Vol 283 (4) ◽

pp. G965-G974 ◽

Cited By ~ 28

Author(s):

Yuxiang Ma ◽

Robert D. Specian ◽

Kwo-Yih Yeh ◽

Mary Yeh ◽

Juan Rodriguez-Paris ◽

...

Keyword(s):

Iron Transport ◽

Brush Border Membrane ◽

Divalent Metal ◽

Apical Surface ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Intestinal Epithelia ◽

Metal Transporter ◽

Apical Chamber ◽

Texas Red

Caco-2 cells grown in bicameral chambers are a model system to study intestinal iron absorption. Caco-2 cells exhibit constitutive transport of iron from the apical (luminal) chamber to the basal (serosal) chamber that is enhanced by apo-transferrin in the basal chamber, with the apo-transferrin undergoing endocytosis to the apical portion of the cell. With the addition of iron to the apical surface, divalent metal transporter 1 (DMT1) on the brush-border membrane (BBM) undergoes endocytosis. These findings suggest that in Caco-2 cells DMT1 and apo-transferrin may cooperate in iron transport through transcytosis. To prove this hypothesis, we determined by confocal microscopy that, after addition of iron to the apical chamber, DMT1 from the BBM and Texas red apo-transferrin from the basal chamber colocalized in a perinuclear compartment. Colocalization was also observed by isolating endosomes from Caco-2 cells after ingestion of ultra-small paramagnetic particles from either the basal or apical chamber. The isolated endosomes contained both transferrin and DMT1 independent of the chamber from which the paramagnetic particles were endocytosed. These findings suggest that iron transport across intestinal epithelia may be mediated by transcytosis.

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Transgenic Mice Overexpressing the Divalent Metal Transporter 1 Exhibit Iron Accumulation and Enhanced Parkin Expression in the Brain

NeuroMolecular Medicine ◽

10.1007/s12017-017-8451-0 ◽

2017 ◽

Vol 19 (2-3) ◽

pp. 375-386 ◽

Cited By ~ 11

Author(s):

Cheng-Wu Zhang ◽

Yee Kit Tai ◽

Bing-Han Chai ◽

Katherine C. M. Chew ◽

Eng-Tat Ang ◽

...

Keyword(s):

Transgenic Mice ◽

Divalent Metal ◽

Iron Accumulation ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

The Brain

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Endothelial cells are critical regulators of iron transport in a model of the human blood–brain barrier

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18783372 ◽

2018 ◽

Vol 39 (11) ◽

pp. 2117-2131 ◽

Cited By ~ 17

Author(s):

Brian Chiou ◽

Emma H Neal ◽

Aaron B Bowman ◽

Ethan S Lippmann ◽

Ian A Simpson ◽

...

Keyword(s):

Endothelial Cells ◽

Iron Deficiency ◽

Blood Brain Barrier ◽

Iron Transport ◽

Brain Barrier ◽

Brain Iron ◽

Blood Brain ◽

Iron Delivery ◽

The Impact ◽

The Brain

Iron delivery to the brain is essential for multiple neurological processes such as myelination, neurotransmitter synthesis, and energy production. Loss of brain iron homeostasis is a significant factor in multiple neurological disorders. Understanding the mechanism by which the transport of iron across the blood–brain barrier (BBB) is regulated is crucial to address the impact of iron deficiency on brain development and excessive accumulation of iron in neurodegenerative diseases. Using induced pluripotent stem cell (iPSC)-derived brain endothelial cells (huECs) as a human BBB model, we demonstrate the ability of transferrin, hepcidin, and DMT1 to impact iron transport and release. Our model reveals a new function for H-ferritin to transport iron across the BBB by binding to the T-cell immunoglobulin and mucin receptor 1. We show that huECs secrete both transferrin and H-ferritin, which can serve as iron sources for the brain. Based on our data, brain iron status can exert control of iron transport across the endothelial cells that constitute the BBB. These data address a number of pertinent questions such as how brain iron uptake is regulated at the regional level, the source of iron delivery to the brain, and the clinical strategies for attempting to treat brain iron deficiency.

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