Astrocytes are considered key regulators of the iron metabolism of the brain. These cells are able to rapidly accumulate iron ions and various iron-containing compounds, store iron efficiently in ferritin and also export iron. The present short review summarizes our current knowledge of the molecular mechanisms involved in the handling of iron by astrocytes. Cultured astrocytes efficiently take up iron as ferrous or ferric iron ions or as haem by specific iron transport proteins in their cell membrane. In addition, astrocytes accumulate large amounts of iron oxide nanoparticles by endocytotic mechanisms. Despite the rapid accumulation of high amounts of iron from various iron-containing sources, the viability of astrocytes is hardly affected. A rather slow liberation of iron from accumulated haem or iron oxide nanoparticles as well as the strong up-regulation of the synthesis of the iron storage protein ferritin are likely to contribute to the high resistance of astrocytes to iron toxicity. The efficient uptake of extracellular iron by cultured astrocytes as well as their strong up-regulation of ferritin after iron exposure also suggests that brain astrocytes deal well with an excess of iron and protect the brain against iron-mediated toxicity.

Introduction

Astrocytes are considered key regulators of the metabolism of the essential redox-active metals iron and copper in the brain [1,2]. Owing to their ability to efficiently accumulate iron ions, to store excess of iron in ferritin and to export iron, they are perfectly suited to regulate the iron distribution within the brain and to protect other types of brain cells against iron-mediated toxicity [1,3]. Astrocytes almost completely cover the brain capillaries with their endfeet and thus have a strategically important location as the first parenchymal cell type of the brain to encounter iron ions and iron-containing compounds that have crossed the blood–brain barrier from the blood through the capillary endothelial cells into the brain.

Astrocytes can encounter extracellular iron in various forms. Ferrous or ferric iron ions are present in the extracellular space as low-molecular-mass iron complexes [4,5] or are bound to proteins such as Tf (transferrin) [6]. In addition, astrocytes have contact with haem-bound iron that is derived from damaged brain cells or from blood cells after haemorrhagic stroke [7]. Furthermore, astrocytes will encounter IONPs (iron oxide nanoparticles) that are applied for analytical or therapeutic reasons [8]. The present short review gives an update on our current knowledge of the uptake and the cellular metabolism of different iron sources in astrocytes, with a focus on recent reports on the uptake and metabolism of haem and IONPs in astrocytes.

Uptake of iron into astrocytes

Cultured astrocytes have been reported to efficiently accumulate iron after application of ferrous or ferric iron salts, haemin or IONPs (Figure 1). In the present review, we focus predominately on recently published results. For a more detailed description of this topic, the reader is referred to other review articles [1,7,8].

Uptake and metabolism of iron in cultured astrocytes

Figure 1
Uptake and metabolism of iron in cultured astrocytes

Astrocytes are able to accumulate iron from various exogenous iron sources. Haem-bound iron uptake is mediated by HCP1 and iron is liberated from internalized haem by HO-1. NTBI can be taken up by an as yet unknown ferric iron (Fe3+) transporter or can be reduced by extracellular reductases or ascorbate. Extracellular ferrous iron (Fe2+) can be taken up by DMT1. Cultured astrocytes take up Tf-bound ferric iron via the Tf–TfR complex into endosomes. The ferric iron released from the Tf–TfR complex is reduced to ferrous iron and subsequently exported into the cytosol by DMT1. In addition, astrocytes efficiently internalize IONPs by endocytotic mechanisms and store these particles in vesicular structures. Low-molecular-mass iron that has been taken up into the cells or is generated from internalized haem or IONPs enters the labile cellular iron pool. From this pool iron can be used for incorporation into haem groups and iron–sulfur (Fe–S) clusters, whereas excess of iron can be stored in a redox-inactive form in ferritin or can be exported by the iron exporter ferroportin. Ferrous iron that is exported by ferroportin is immediately oxidized by the membrane-bound glycosylphosphatidylinositol-anchored form of caeruloplasmin (GPI-Cp). The question mark (?) identifies steps in iron metabolism that have not been experimentally confirmed for astrocytes to date.

Figure 1
Uptake and metabolism of iron in cultured astrocytes

Astrocytes are able to accumulate iron from various exogenous iron sources. Haem-bound iron uptake is mediated by HCP1 and iron is liberated from internalized haem by HO-1. NTBI can be taken up by an as yet unknown ferric iron (Fe3+) transporter or can be reduced by extracellular reductases or ascorbate. Extracellular ferrous iron (Fe2+) can be taken up by DMT1. Cultured astrocytes take up Tf-bound ferric iron via the Tf–TfR complex into endosomes. The ferric iron released from the Tf–TfR complex is reduced to ferrous iron and subsequently exported into the cytosol by DMT1. In addition, astrocytes efficiently internalize IONPs by endocytotic mechanisms and store these particles in vesicular structures. Low-molecular-mass iron that has been taken up into the cells or is generated from internalized haem or IONPs enters the labile cellular iron pool. From this pool iron can be used for incorporation into haem groups and iron–sulfur (Fe–S) clusters, whereas excess of iron can be stored in a redox-inactive form in ferritin or can be exported by the iron exporter ferroportin. Ferrous iron that is exported by ferroportin is immediately oxidized by the membrane-bound glycosylphosphatidylinositol-anchored form of caeruloplasmin (GPI-Cp). The question mark (?) identifies steps in iron metabolism that have not been experimentally confirmed for astrocytes to date.

Uptake of ferrous and ferric iron

Astrocytes have been shown to accumulate NTBI (non-transferrin-bound iron) from ferrous iron [9,10] and ferric iron [1012]. Currently it is unclear which transporter is involved in the uptake of ferric iron [10,13]. In contrast, DMT1 (divalent metal transporter 1) is considered to be involved in the uptake of ferrous iron into astrocytes [9,14,15]. The DMT1 substrate ferrous iron is provided for astrocytic uptake by the reduction of ferric iron by either a membrane-based ectoreductase [9] or ascorbate that is released from astrocytes [10]. Two DMT1 isoforms, which either contain or do not contain an iron-response element, have been reported to be expressed in astrocytes in vivo [16].

Uptake of NTBI into astrocytes is inhibited by carboxylates, such as citrate, tartrate or malate, most probably due to their ability to complex iron, thereby lowering the access of the iron transporter to the complexed iron [15]. In addition, the zinc transporter Zip14 [14] and resident transient receptor potential channels [17] have been suggested to be involved in the uptake of NTBI by astrocytes. An involvement of the latter of these transporters would connect iron accumulation with synaptic activity. Such an NTBI uptake into astrocytes could help to prevent a spillover of iron into the synaptic cleft, thereby protecting neurons [17]. The uptake of NTBI into astrocytes is modulated by alterations in the expression of proteins that are involved in iron import, for example by hypoxia [18], cytokines, such as TNF-α (tumour necrosis factor-α) and IL (interleukin)-1β [17,19], or by the presence of hepcidin [20].

In contrast with other brain cells, astrocytes in vivo do not appear to express either Tf or TfR1 (Tf receptor 1) [21,22], whereas in astrocyte cultures both proteins are expressed and can contribute to the accumulation of Tf-bound ferric iron [23,24].

Haem uptake

Uptake of haem into cells can be mediated by endocytotic uptake of a haemopexin–haem complex as well as by the membrane transporter HCP1 (haem carrier protein 1) [7]. The low-density lipoprotein receptor, which is involved in the uptake of the haemin–haemopexin complex, is known to be expressed in astrocytes [25], but it is not known whether this mechanism of haem uptake takes place in astrocytes [7]. In contrast, HCP1 has been reported to contribute to the haemin accumulation by cultured astrocytes [26,27]. Accumulation of higher amounts of haemin by astrocytes compromises their viability [28,29]. ROS (reactive oxygen species) formation by iron ions liberated from accumulated haemin as well as iron-independent mechanisms have been suggested to contribute to the observed haemin toxicity in astrocytes [7,2830].

Uptake of IONPs

Magnetic IONPs have gained a fair amount of attention in recent years due to their application in neurobiology and medicine, as such particles are used as contrast agents in MRI, for the MRI-based cell tracking of IONP-loaded cells, for magnetic-field-directed drug targeting to tumours across the blood–brain barrier and for direct anti-tumour treatment by magnetic fluid hyperthermia [31]. For stable dispersion in physiological fluids, IONPs have to be coated with low-molecular-mass organic compounds, organic polymers or proteins. Cultured astrocytes efficiently accumulate IONPs with various types of coatings in a time-, concentration- and temperature-dependent manner (for an overview, see [8]) with saturable uptake kinetics [32]. Owing to their magnetic properties, the uptake of IONPs into astrocytes was increased in the presence of a static magnetic field induced by a magnet that was placed underneath the cells [33,34]. The surface charge of IONPs strongly affects particle uptake. IONPs with a positive surface charge are more efficiently accumulated by astrocytes than negatively charged IONPs [34]. In addition, the presence of serum proteins strongly affects the surface charge by formation of a protein corona around the particles. This alteration in the physicochemical surface properties of IONPs affects the binding of IONPs to the cells and subsequently lowers their internalization into astrocytes [35].

Accumulated IONPs are present in astrocytes in intracellular vesicles [32,3639], strongly suggesting that endocytotic processes mediate IONP uptake into astrocytes. Indeed, the accumulation of IONPs in presence of serum was strongly affected by inhibitors of macropinocytosis and clathrin-mediated endocytosis [35], demonstrating that these pathways are involved at least in the uptake of protein-coated IONPs. However, such inhibitors did not affect the highly efficient uptake of IONPs in serum-free conditions [33,35], suggesting that a further, as yet unidentified, endocytotic process is responsible for the strong IONP accumulation by astrocytes in serum-free conditions.

Metabolism of haem and IONPs in astrocytes

Viable cultured astrocytes have been reported to increase their specific iron content up to 9-fold if they are exposed to haemin [26]. The enzyme responsible for cellular metabolism of haem is HO-1 (haem oxygenase-1), which degrades haemin into biliverdin, carbon monoxide and iron. Although HO-1 is up-regulated in astrocytes upon exposure to haemin [28,40], only approximately 20% of the accumulated haemin is metabolized by astrocytes as shown by the increase in non-haemin-bound iron [28]. Nevertheless, iron was liberated from internalized haemin in cultured astrocytes at least in concentrations that are sufficient to induce the up-regulation of the iron storage protein ferritin.

Astrocytes have been shown to increase their specific iron content up to 1000-fold if they are exposed to high concentrations of IONPs [32,33]. However, such a treatment did not compromise the viability of the cells or their glucose or glutathione metabolism [41]. IONPs that are accumulated by astrocytes in cell culture [41] or in the brain [42,43] appear to remain largely intact in these cells. At 7 days after exposure of cultured astrocytes to IONPs, most of the internalized IONPs were detected as electron-dense particles in vesicles and no substantial amounts of iron or IONPs were released from the cells [41], suggesting that most of the accumulated IONPs are still intact and that little iron has been liberated from the accumulated IONPs. Nevertheless, some iron is liberated in astrocytes from the internalized IONPs as indicated by the transient appearance of ROS and the strong up-regulation of ferritin synthesis [41]. This liberation of iron from accumulated IONPs is likely to occur in the lysosomes, since their acidic pH and the presence of reducing compounds will foster IONP degradation and ferrous iron generation, which is subsequently exported into the cytosol via DMT1 [8]. In the cytosol, IONP-derived iron ions can be stored in ferritin, catalyse ROS generation and/or be used for iron-dependent cellular processes, including proliferation [41,44]. However, iron liberation from accumulated IONPs in astrocytes does not appear to generate sufficient amounts of ferrous iron to enable ferroportin-mediated export of iron [41].

Storage of iron in ferritin

An increase in the cellular concentration of the low- molecular-mass iron pool induces the synthesis of the iron storage protein ferritin [13]. This post-translational up-regulation of ferritin synthesis has been observed in astrocytes in pathological brain tissue as well as in cultured astrocytes treated with various stimuli [1]. For example, iron storage in astrocytes is increased by the pro-inflammatory cytokine TNF-α [19]. In cultured astrocytes, the level of ferritin is increased after the application of low-molecular-mass iron [19,23], haemin [28,30] or IONPs [41]. As the iron-dependent up-regulation of ferritin synthesis depends on the presence of an excess of low-molecular-mass iron [13], the elevated ferritin levels in astrocytes treated with haemin or IONPs can be considered a clear indication of a liberation of iron from internalized haemin or IONPs.

Export of iron from astrocytes

Export of iron from astrocytes is mediated by ferroportin. This process has been discussed to be important for the supply of iron to other brain cell types such as neurons [1]. Recently, ferroportin-mediated iron export from astrocytes has also been shown to be involved in remyelination [45]. Ferroportin requires ferrous iron as substrate, but its export is directly coupled with its extracellular oxidation by a glycosylphosphatidylinositol-anchored form of caeruloplasmin [13]. Accordingly, caeruloplasmin deficiency impairs the iron export from cultured astrocytes [46].

Cellular iron export by ferroportin is regulated by the hormone hepcidin, which controls the level of ferroportin in the plasma membrane by inducing its internalization and degradation [13]. In addition for astrocytes, hepcidin has been reported to decrease cellular ferroportin levels and iron release [20,47]. In contrast, TGF (transforming growth factor)-β1 induces iron efflux from astrocytes by increasing ferroportin expression [19]. Furthermore, oxidative modification of caeruloplasmin [48] and oxidative-stress-induced down-regulation of this enzyme in astrocytes [49] have been discussed to impair iron export from astrocytes.

Conclusions

Owing to their ability to efficiently accumulate extracellular iron, to store excess of iron in ferritin and to release iron, astrocytes are equipped with the machinery to regulate iron metabolism in the brain. Astrocytes, at least in culture, are highly efficient in accumulating large amounts of haem iron and of IONPs. The slow liberation of iron from accumulated haem and IONPs is likely to prevent extensive iron-mediated ROS production of exposed astrocytes, thereby giving these cells the time to up-regulate the synthesis of ferritin in order to enable the cells to safely store the iron liberated from internalized haem and IONPs in a redox-inactive form in ferritin. For IONPs, the compartmentalization of the accumulated nanoparticles in vesicles is likely to contribute to the observed remarkable resistance of astrocytes to IONP toxicity. This efficient handling of haem and IONPs by cultured astrocytes also suggests that the astrocytes in the brain will deal well with such compounds, thereby protecting other types of brain cells against iron toxicity.

5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders: A joint Biochemical Society/European Society for Neurochemistry Focused Meeting held at the University of Bath, U.K., 23–26 June 2013. Organized and Edited by Marcus Rattray (University of Bradford, U.K.) and Rob Williams (University of Bath, U.K.).

Abbreviations

     
  • DMT1

    divalent metal transporter 1

  •  
  • HCP1

    haem carrier protein 1

  •  
  • HO-1

    haem oxygenase-1

  •  
  • IONP

    iron oxide nanoparticle

  •  
  • NTBI

    non-transferrin-bound iron

  •  
  • ROS

    reactive oxygen species

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • Tf

    transferrin

  •  
  • TfR

    Tf receptor

Funding

Our work was supported by ‘Forschungsförderung’ of the University of Bremen (to M.C.H.).

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