Glial Cell Ceruloplasmin and Hepcidin Differentially Regulate Iron Efflux from Brain Microvascular Endothelial Cells

McCarthy, Ryan C.; Kosman, Daniel J.

doi:10.1371/journal.pone.0089003

Cited by 91 publications

(132 citation statements)

References 65 publications

(99 reference statements)

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…Here, we show that the physiological response invoked by iron-deficient astrocytes includes elevation of total iron levels in human brain microvascular endothelial cells. Recently, other groups have addressed paracrine signal-dependent release of iron from endothelial cells via ferroportin (14,15). However, iron acquisition by hBMVECs as a part of this response has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine factors released by neighboring astrocytes communicate iron status of the brain to BMVECs (14,15). In vitro studies have so far identified hepcidin, ceruloplasmin, interleukin-6, soluble amyloid precursor protein, and holo-transferrin as some of the candidates in astrocyte secretome that communicate iron status to BMVECs (14 -16).…”

Section: Edited By Paul E Frasermentioning

confidence: 99%

“…Paracrine factors released by glia are known to regulate the expression of iron homeostasis proteins in endothelial cells (14,15). We used a Transwell system to mimic the BBB in vitro to test the effect of iron-conditioned glial cell medium on NHE9 expression in hBMVECs (14,15,39).…”

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

“…We used a Transwell system to mimic the BBB in vitro to test the effect of iron-conditioned glial cell medium on NHE9 expression in hBMVECs (14,15,39). This cell line is commonly used in BBB models (15,40,41). hBMVECs are polarized, with their apical surface facing the blood and their basal surface facing the brain parenchyma.…”

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

“…2D). Next, we cultured C6 glioma cells, a commonly used astrocytic model in co-cultures with BMVECs (15,(42)(43)(44), in iron-conditioned medium (Fig. 3A).…”

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

See 4 more Smart Citations

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Paul E. FraserIron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.There is high demand for iron in the brain, one of the most metabolically active organs in the body (1, 2). Iron is a co-factor of several proteins involved in specialized brain cell functions such as synthesis of neurotransmitters and myelination (3-5). Iron is also necessary for housekeeping functions such as mitochondrial respiration and DNA synthesis, crucial for brain function (5). Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10, 11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).Iron entry into the brain is regulated by the blood-brain barrier (BBB) 3 (10). This physiological barrier is characterized by tight junctions between brain microvascular endothelial cells (BMVECs) that block passive diffusion of iron into the brain (12). BMVECs are polarized cells with one surface (apical) facing the blood and the other (basal or abluminal) facing interstitial fluid of the brain. BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2, 13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine fac...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Edited By Paul E Frasermentioning

confidence: 99%

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

“…2D). Next, we cultured C6 glioma cells, a commonly used astrocytic model in co-cultures with BMVECs (15,(42)(43)(44), in iron-conditioned medium (Fig. 3A).…”

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

See 3 more Smart Citations

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Advances in Modeling Alzheimer's Disease In Vitro

Sharma

Karan

Lee

et al. 2021

Advanced NanoBiomed Research

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss and cognitive impairment, thereby disrupting the performance of daily activities. Numerous therapeutics have shown efficacy in animal AD models but failed in human patients. The key to understanding the etiology of AD lies in the development of effective disease models, which can ideally recapitulate all characteristics of the disease. Over the years, different approaches including in vitro, in vivo, and in silico models are able to resemble certain features of AD. In this review, the significance of different in vitro models including their merits and limitations in modeling AD is discussed, which will give a better perspective on the development of a comprehensive model that can mimic human AD. This starts with a brief introduction to AD and its pathology. Then it mainly focuses on the two‐dimensional, three‐dimensional and microfluidic in vitro models of AD that have made significant advancements in understanding AD pathology and aiding in screening effective therapeutics. Several 3D neural tissue engineering models developed in the last two decades along with a discussion on the future prospects in the development of efficient in vitro AD models are further highlighted.

show abstract

Hepcidin and its potential clinical utility

Miseta

Nagy

et al. 2015

Cell Biology International

View full text Add to dashboard Cite

A number of pathophysiological conditions are related to iron metabolism disturbances. Some of them are well known, others are newly discovered or special. Hepcidin is a newly identified iron metabolism regulating hormone, which could be a promising biomarker for many disorders. In this review, we provide background information about mammalian iron metabolism, cellular iron trafficking, and the regulation of expression of hepcidin. Beside these molecular biological processes, we summarize the methods that have been used to determine blood and urine hepcidin levels and present those pathological conditions (cancer, inflammation, neurological disorders) when hepcidin measurement may have clinical relevance.

show abstract

Glial Cell Ceruloplasmin and Hepcidin Differentially Regulate Iron Efflux from Brain Microvascular Endothelial Cells

Cited by 91 publications

References 65 publications

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Advances in Modeling Alzheimer's Disease In Vitro

Hepcidin and its potential clinical utility

Contact Info

Product

Resources

About