Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neurochem. Author manuscript; available in PMC 2013 January 1.
Published in final edited form as:
PMCID: PMC3295237

Pathogenic implications of iron accumulation in multiple sclerosis


Iron, an essential element used for a multitude of biochemical reactions, abnormally accumulates in the central nervous system of patients with multiple sclerosis (MS). The mechanisms of abnormal iron deposition in MS are not fully understood, nor do we know whether these deposits have adverse consequences, i.e., contribute to pathogenesis. With some exceptions, excess levels of iron are represented concomitantly in multiple deep gray matter structures often with bilateral representation, while in white matter pathological iron deposits are usually located at sites of inflammation that are associated with veins. These distinct spatial patterns suggest disparate mechanisms of iron accumulation between these regions. Iron has been postulated to promote disease activity in MS by various means: 1) iron can amplify the activated state of microglia resulting in the increased production of proinflammatory mediators; 2) excess intracellular iron deposits could promote mitochondria dysfunction; and 3) improperly managed iron could catalyze the production of damaging reactive oxygen species. The pathological consequences of abnormal iron deposits may be dependent on the affected brain region and/or accumulation process. Here we review putative mechanisms of enhanced iron uptake in MS and address the likely roles of iron in the pathogenesis of this disease.

Keywords: DMT-1, experimental autoimmune encephalomyelitis, ferritin, neurodegeneration, microglia, proinflammatory cytokines, reactive oxygen species, transferrin receptor


Iron is utilized in a large array of biochemical processes necessary for normal brain function, e.g., iron serves as a cofactor for enzymes involved in neurotransmitter metabolism (Crichton et al. 2011), it is utilized by enzymes involved in myelin synthesis (Todorich et al. 2009), iron is part of the electron transport chain (Richardson et al. 2010), etc. Iron is also thought to perform key roles in repair mechanisms (e.g., remyelination, mitochondrial biogenesis) in response to diseases of the central nervous system (CNS). Excess iron can promote inflammatory states of macrophages and microglial cells, which could be beneficial in combating an infection, but can have a negative effect in multiple sclerosis (MS) where inflammation is a significant component of the pathological profile. In conditions where iron concentrations reach excessive levels or iron is mishandled, there can be enhanced generation of damaging reactive oxygen species (ROS) leading to neurodegeneration (Crompton et al. 2002; Barbeito et al. 2009; Deng et al. 2010).

Abnormally high levels of iron have been detected in both gray and white matter regions in the CNS of patients with MS. Abnormal iron deposits can occur as extracellular deposits associated with cell debris (e.g., as a consequence of demyelination or degeneration) or as extravasated red blood cells (RBCs) and their breakdown products. In addition, iron can abnormally accumulate in mitochondria, microglia, macrophages, neuropil, neurons, and along vessels. Since iron can facilitate inflammation and act as a catalyst for the production of damaging ROS, it is tempting to speculate that its enhanced deposition advances the pathological course of MS. In support of this view, several studies indicate a pathogenic role of oxidative damage in MS (LeVine and Chakrabarty 2004) and the level of iron deposition correlates with markers of disease progression (Bakshi et al. 2000; Bermel et al. 2005; Tjoa et al. 2005; Brass et al. 2006a; Zhang et al. 2007; Neema et al. 2009). Here we review how iron is thought to accumulate in MS and address iron’s putative roles in the pathogenesis of disease.

Iron deposition in MS gray matter

MRI has been used to assess relative concentrations of iron in the CNS. Iron accumulation in the brain causes a reduction (shortening) in T2 relaxation times, resulting in a hypointensity on T2-weighted images (Brass et al. 2006b). A greater hypointensity is associated with enhanced deposition as occurs with age or in various disease states (Brass et al. 2006b). In MS subjects, MRI studies have found abnormal T2-weighted shortenings in several areas (e.g., thalamus, putamen, caudate, Rolandic cortex) (Drayer et al. 1987a, b; Grimaud et al. 1995; Russo et al. 1997; Bakshi et al. 2000) in a substantial percentage of patients. In one study, 42% and 57% of MS patients had a T2 hypointensity in the putamen and thalamus, respectively, with a lower percentage observed in the caudate and Rolandic cortex (Bakshi et al. 2000). Other MRI methods, such as magnetic field correlation (MFC), R2* relaxometry or susceptibility weighted imaging (SWI), have also revealed iron accumulation in gray matter structures of MS subjects (Brass et al. 2006b, Ge et al. 2007; Haacke et al. 2009, 2010a; Khalil et al. 2009). In some instances, signals representative of iron could be seen with MFC but not as a standard T2 hypointensity (Ge et al. 2007) suggesting that the percentage of MS patients with iron deposition detected by a T2 hypointensity is an underestimation. MFC also revealed sizable changes in signal intensities between MS and healthy controls: globus pallidus (24%), thalamus (30.6%) and putamen (39.5%) (Ge et al. 2007).

The iron content in the brain is related to age in normal individuals. Thus, adjusting for age effects on iron accumulation in MS is paramount in order to distinguish the relative contribution due to aging vs. the disease process. An early study found that iron concentrations increase rapidly to ~30–40 years, and then the accumulation in several structures plateaus or slows with advancing age (Hallgren and Sourander, 1958). However, a study using a combination approach (e.g., T2* magnitude and SWI phase data analyses) has shown that the iron content continues to increase with advancing age particularly in structures known to have a high iron content (Haacke et al. 2010b). Thus, a combination of techniques might be a useful way to more accurately measure the effects of the disease state on the abnormal accumulation of iron (Haacke et al., 2010b).

Several measures of MS disease activity (e.g., brain atrophy, expanded disability status scale) have been correlated with MRI signals of iron detection in deep gray matter structures, and this correlation has been suggested to reflect an association between iron deposition and disease progression (Bakshi et al. 2000; Bermel et al. 2005; Tjoa et al. 2005; Brass et al. 2006a; Ge et al. 2007; Zhang et al. 2007; Neema et al. 2009). However, the effect size of the correlations were often small or modest suggesting that iron deposition may not be a main determinant affecting the disease parameter being measured (Bermel et al. 2005; Tjoa et al. 2005; Brass et al. 2006a; Ge et al. 2007; Zhang et al. 2007). On the other hand, the T2 hypointensity predicted the disease course and disability better than standard MRI measures (Bakshi et al. 2002). Disease duration positively correlates with MRI signs of iron deposition (Bakshi et al. 2000), and secondary progressive multiple sclerosis (SPMS) patients were reported to have a greater level of iron accumulation, i.e., more abnormal T2 hypointensities, than relapsing remitting multiple sclerosis (RRMS) patients (Bakshi et al. 2000, 2002). This difference, however, was not observed between subjects with benign MS and SPMS. T2 hypointensities were similar between these conditions, but clinical and pathological (such as brain atrophy) features were more severe in SPMS even though the patients with benign MS had a longer duration of disease (Ceccarelli et al. 2009). It is likely that the milder level of disease activity in benign MS offset the impact of longer disease duration.

In control subjects, it is unclear if there are differences in MRI signal intensities indicative of iron between left and right corresponding structures as one study found no differences (Ceccarelli et al. 2009) while another found greater concentrations in the left sided structures (Xu et al. 2008). A histochemical study noted more iron in the left hemisphere than the right in control subjects (Langkammer et al. 2010).

MRI studies of MS brains have shown that the accumulation of abnormal deep gray matter iron deposits is usually represented in both hemispheres (Bakshi et al. 2002; Khalil et al. 2009), but the relative intensity between the left and right structures may differ. Although no left-right differences for iron deposition were observed in RRMS subjects (Khalil et al. 2009), differences between left and right structures were seen in SPMS and benign MS (Ceccarelli et al. 2009). In clinically isolated syndrome, one study found no left-right difference (Khalil et al. 2009) while another did (Ceccarelli et al. 2010), and iron accumulation was apparent in the left head of the caudate nucleus but not on the right head in patients with pediatric MS (Ceccarelli et al. 2011). Intra-subject left-right differences were noted for iron deposition in some structures, e.g., putamen and globus pallidus, but not for others, e.g., caudate and thalamus, in MS patients (Bermel et al. 2005).

Future studies examining whether left-right differences correspond to pathways interrupted by axonal transection or neuronal loss could provide insights regarding the mechanism of iron accumulation. Of note, the caudate, putamen, thalamus, and globus pallidus all displayed a significant elevation in iron deposition in SPMS compared to controls (Ceccarelli et al. 2009) suggesting a linkage in the events that affected these structures. Since these structures are all interconnected (Alexander and Crutcher 1990; Silkis 2001; Miyachi et al. 2006), it is possible that disruption of one pathway or structure can affect neuronal degeneration (Prinster et al. 2006) and/or iron metabolism in others, which would be somewhat similar to observations in experimental models of neurodegeneration (Shoham et al. 1992; Sastry and Arendash 1995). To investigate the mechanism of iron accumulation, it would be relevant to determine if the iron transport protein divalent metal transporter 1 (DMT1) is upregulated in deep gray matter structures in MS, as appears to be the case for the substantia nigra in Parkinson disease (PD) (Salazar et al. 2008) which also has abnormally increased iron deposition (Gotz et al. 2004).

Cerebrospinal fluid (CSF) and serum levels of iron are not increased in MS subjects (LeVine et al. 1999; Sfagos et al. 2005; Abo-Krysha and Rashed 2008), and several studies have failed to detect an association between alleles of the hemochromatosis gene and MS (Ristić et al. 2005; Kotze et al. 2006; Ramagopalan et al. 2008). However, levels of the iron storage protein ferritin in the CSF or blood are increased in SPMS subjects compared to normal controls (LeVine et al. 1999; Petzold et al. 2002; Sfagos et al. 2005; Worthington et al. 2010), and elevated levels of ferritin were also observed in brain tissue homogenates from MS subjects (Petzold et al. 2002). Proinflammatory cytokines that are elevated in MS [e.g., tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and/or interleukin-6 (IL-6)], are known to induce ferritin production in a variety of cell types (Rogers et al. 1990; Tsuji et al. 1991; Smirnov et al. 1999). Additionally, the enhanced accumulation of brain iron could facilitate the enhanced production ferritin. Elevated ferritin levels are thought to have a protective function (LeVine et al. 2002). For example, ferritin can store excess iron and limit iron-catalyzed oxidative reactions leading to cellular damage (Balla et al. 1992; Juckett et al. 1995), and ferritin has been shown to suppress immune cell function (Matzner et al. 1979; Keown and Descamps-Latscha 1983; Harada et al. 1987) that could promote disease activity. Indeed, Worthington et al. (2010) showed that increased CSF ferritin levels over time correlated with improvements on T2 lesion volume and possibly the ambulation index.

Iron deposition in MS white matter

Extensive lymphocyte cuffing, macrophage infiltration, and fibrin deposits are localized around veins in active MS lesions (Putnam 1937; Tanaka et al. 1975; Adams 1989; Adams et al. 1989; Wakefield et al. 1994), and histochemical (Craelius et al. 1982; Adams 1988, 1989; Zamboni 2006) and SWI MRI (Haacke et al. 2009, 2010a) studies have identified abnormal iron deposits in perivenular locations in white matter. Perivascular iron deposits, revealed by histochemistry, were associated with active or inactive lesions in 17% and 30% of MS subjects, respectively (Adams 1988); however, these frequencies may be under represented due to technical considerations related to tissue processing (LeVine 1997; LeVine and Chakrabarty 2004) or tissue sampling, and findings by SWI support a greater frequency of iron ladened structures in MS subjects (Haacke et al. 2009, 2010a). Besides occasional exceptions (Russo et al. 1997), abnormal iron deposits in white matter are not thought to have bilateral spatial representations in both hemispheres, unlike the findings for deep gray matter structures (Russo et al. 1997; Haacke et al. 2009; 2010a; Khalil et al. 2009). In addition to labeling around vessels, iron deposits are found in reactive microglia, macrophages and transected axons of MS patients (Craelius et al. 1982; Adams 1988, 1989; LeVine 1997). These varying distribution patterns of abnormal iron deposits between white matter and deep gray matter structures suggest different mechanisms of iron accumulation for these areas.

CNS iron deposits in animal models of MS or neurodegeneration

Abnormal CNS iron deposits are present in both gray and white matter structures in various animal models of MS. In mice with experimental autoimmune encephalomyelitis (EAE), iron histochemical staining is typically associated with vessels, reactive microglia, and macrophages, although granular deposits and extravasated RBCs are also labeled (Forge et al. 1998; Pedchenko and LeVine 1998). These features are observed during the active stage of disease as well as partially present during the recovery phase (Forge et al. 1998). EAE in rodents typically affects the spinal cord and hind brain to a greater extent than the cerebrum. Thus, standard rodent models may not be suitable for investigations of iron accumulation in cerebral structures. However, in a recently developed cerebral EAE model, a targeted intracranial injection of cytokines to the subcortical white matter of mice with EAE led to substantial pathology including abnormal iron accumulation in both cerebral hemispheres (Williams et al. 2011). In the marmoset EAE model, T2 hypointense areas developed in deep gray matter structures at 57 days post-encephalitogen injection (Boretius et al. 2006). The T2 hypointense areas are indicative of iron deposits similar to that described for humans with MS, and these gray matter changes occurred in conjunction with subcortical white matter lesions in the cerebrum (Boretius et al. 2006) suggesting an interrelationship of the pathological events between these structures.

Cortical pathology or lesions in subcortical white matter, e.g., axonal transection, can lead to denervation and/or axotomization of deep gray matter structures, such as the thalamus, resulting in loss of trophic support and/or presence of other stresses that may signal the uptake of iron (discussed in subsequent section). Indeed, experimental evidence supports the development of iron accumulation in deep gray matter structures following cortical or subcortical white matter lesions. In an MS animal model that utilized an intracerebral injection of Theiler’s virus, animals had ventricular enlargement indicative of brain atrophy and a T2 hypointensity developed in the thalamus suggesting enhanced iron deposition, but iron histochemical studies were not performed (Pirko et al. 2009, 2011). T2 hypointensities and iron deposition were colocalized in the thalamus in a mouse model of traumatic brain injury to the sensorimotor cortex (Onyszchuk et al. 2009) indicating that the T2 hypointensity seen in the thalamus of mice given Theiler’s virus (Pirko et al. 2009) could similarly be due to iron accumulation. Thalamic pathology was present in an EAE model that incorporated cortical cryolesions, but again studies on iron deposition were not performed (Sun et al. 2000). In the cerebral EAE model, iron deposits were present around some cortical vessels and associated with some inflammatory lesion sites. These pathological iron deposits could be detected by MRI as T2 hypointensities. Iron deposits were also present within reactive microglia (Williams et al. 2011). Other studies have preloaded macrophages with exogenous iron and utilized MRI to detect the infiltration of cells into the CNS of EAE animals (Dousset et al. 1999; Floris et al. 2004; Rausch et al. 2004; Stoll et al. 2004; Brochet et al. 2006; Oweida et al. 2007; Baeten et al. 2008; Chin et al. 2009), but findings from this method should not be confused with those on naturally occurring iron deposition during EAE (Forge et al. 1998; Pedchenko and LeVine 1998; Williams et al. 2011).

Potentially similar to denervation of thalamic neurons, iron accumulates in the substantia nigra zona reticularis following lesions to the neostriatum/globus pallidus complex, and this increase is thought to result from loss of striatal/pallidal inputs (Sastry and Arendash 1995). In another example, lesions to the anterior olfactory nucleus/ventral striatal region resulted in iron accumulation in several deep gray matter structures (Shoham et al. 1992). Elevated levels of iron were also observed in the hippocampus following an intracerebroventricular kainate injection, which produces a model of temporal lobe epilepsy and neuronal degeneration (Ong et al. 1999; Wang et al. 2002). These studies indicate that the loss of inputs/outputs can result in neuronal degeneration and iron accumulation, but it is unclear whether iron deposition promotes the degeneration of neurons.

The accumulation of iron does not appear to be a primary cause of neuronal degeneration in experimental models. For example, at 1 week after a kainate lesion, there was neuronal loss in the CA field but no increases in iron staining (Wang et al. 2002) or iron concentration (Ong et al. 1999) were present in the degenerating field of neurons. By 2 weeks, iron concentrations increased (Ong et al. 1999) and by 1 month there was increased iron staining in the degenerating field, but the staining was in glial cells (Wang et al. 2002). In a neostriatum/globus pallidus complex lesion study, at 1 week post lesion the ipsilateral substantia nigra pars reticularis had an increase in iron staining, which was due to an increase in the number and size of iron stained granules as well as amorphous staining. However, when iron concentrations were measured biochemically, a decrease was noted (Sastry and Arendash 1995). Thus, the changes in iron staining at 1 week may have been due to a redistribution of iron allowing for greater staining, e.g., increased accessibility of histochemical reagents to iron within damaged mitochondria or other structures rather than an increase in iron levels. With time, i.e., 1 month post lesion, the accumulation of iron was observed both histochemically and biochemically in the ipsilateral reticularis, but this accumulation occurred in the presence of extensive neuronal loss and an increase in glial cells (Sastry and Arendash 1995). Although iron accumulation occurred in the neuropil and glia in the basal ganglia following lesions to the anterior olfactory nucleus/ventral striatum, the degeneration of cells could not be linked to iron accumulation (Shoham et al. 1992). Taken together, these results suggest that iron accumulation may be a secondary response to neuronal degeneration. However, the possible redistribution of iron during the early response to injury raises the question whether mismanaged iron promotes neuronal degeneration rather than accumulated iron. Furthermore, it is possible that the accumulation of iron that occurs in response to neuronal degeneration may initiate or promote ongoing damage to other cells.

Mechanisms of iron uptake in gray matter structures in MS and EAE subjects

Neurons and glia are exposed to a variety of acute and prolonged stressful conditions during MS. The proinflammatory environment during an acute exacerbation includes elevated levels of ROS, proinflammatory cytokines, and lipid metabolites. Transected axons and neuronal loss can lead to enduring consequences, such as the denervation of target neurons in MS (Bjartmar and Trapp 2001), which results in a loss of trophic support. Other long-term stresses include altered perfusion and decreased oxygen utilization (Law et al. 2004; Ge et al. 2009), dysfunctional mitochondria (Mahad et al. 2008a; Mao and Reddy 2010) and decreased brain metabolism (Bakshi et al. 1998; Blinkenberg et al. 1999), which can promote an environment for enhanced oxidative stress. Indeed, depletion of the antioxidant glutathione occurs in EAE (Honegger et al. 1989; Chakrabarty et al. 2003) and MS (Calabrese et al. 2003; Srinivasan et al. 2010; Choi et al. 2011) making the brain more susceptible to iron-catalyzed oxidative damage.

In other models of CNS injury, stress associated with hypoxia results in enhanced mitochondria elongation and biogenesis by neurons (Bertoni-Freddari et al. 2006; Yin et al. 2008). Oxidative stress might also promote mitochondrial biogenesis in neurons (Gutsaeva et al. 2006). There have been reports of increased numbers and activity of mitochondria in MS (Witte et al. 2009; Ciccarelli et al. 2010; Geurts and van Horssen 2010) and in experimental models of demyelination (Andrews et al. 2006; Hogan et al. 2009). Biogenesis might be a compensation mechanism that acts to help maintain a normal level of function, e.g., maintain an aerobic set point (Onyango et al. 2010). Since iron is required for enzymes involved in energy production in mitochondria, neuronal iron levels would be predicted to increase. Indeed, punctate iron histochemical staining suggestive of mitochondria was observed in neurons from MS subjects (LeVine 1997).

Since neurons are thought to have limited stores of iron in the form of ferritin (Moos and Morgan 2004), additional iron is required to meet an enhanced need such as that which might occur in response to stress. Neurons take up iron via select mechanisms. Once iron crosses the blood-brain barrier (BBB) it is thought to come into contact with astrocyte endfeet processes where it becomes oxidized to its ferric form by the ferroxidase ceruloplasmin, thereby allowing it to bind to transferrin and enter neurons via the transferrin receptor located at the membrane surface (Crichton et al. 2011). After transferrin-iron binds to the transferrin receptor, this complex invaginates and fuses with endosomes (Moos and Morgan 2004; Crichton et al. 2011). The low pH in the endosomes releases the iron from the transferrin-iron complex. The iron then becomes reduced to the ferrous form via a metalloreductase and DMT1 transports iron into the cytoplasm (Moos and Morgan 2004; Richardson et al. 2010; Crichton et al. 2011). Other possible pathways for iron entry into neurons include uptake of iron-citrate or iron-ATP complexes (Crichton et al. 2011; Wang and Pantopoulos 2011), passage through voltage-gated calcium channels (Gaasch et al. 2007; Pelizzoni et al. 2011), and/or uptake of ferritin through heavy chain subunit (H)-ferritin receptors on neurons (Fisher et al. 2007; Li et al. 2010). For the latter example, the transferrin receptor-1 is a receptor for H-ferritin in humans (Li et al. 2010), and this receptor is expressed by neurons (Moos and Morgan 2004; Chen-Roetling et al. 2011).

Upregulation of the transferrin receptor and/or DMT1 are mechanisms used by neurons to facilitate iron uptake (Moos and Morgan 2000, 2004; Moos et al. 2000, 2007). The transferrin receptor is partially regulated at the post secondary level by iron regulatory proteins (IRPs), which sense the intracellular iron concentration (Wang and Pantopoulos 2011). If the intracellular iron concentration is low, IRPs help stabilize the transferrin receptor mRNA by binding to the iron responsive element (IRE) at the 3′ end, which enables increased translation of the receptor. In addition, the transferrin receptor gene has a hypoxia response element and is activated by hypoxia-inducible factor-1 (Bianchi et al. 1999; Lok and Ponka 1999; Omori et al. 2003) indicating that hypoxic states can facilitate iron uptake. Rapid recycling of the transferrin receptor may also facilitate iron uptake (Crichton et al. 2011; Wang and Pantopoulos 2011).

The soluble transferrin receptor levels in the blood are elevated in MS patients with chronic progressive disease compared to normal subjects and this increase has been speculated to reflect cellular transferrin receptor levels (Sfagos et al. 2005; Abo-Krysha and Rashed 2008). However, examination of MS tissue found normal levels of receptor expression in gray matter together with expression in periplaque regions in white matter (Hulet et al. 1999b) although conclusions should be viewed cautiously as this study was limited to examination of four MS brains. Thus, additional studies are warranted especially on SPMS subjects, as upregulation of the transferrin receptor in gray matter structures could be a mechanism accounting for the elevated levels of iron in these structures (discussed below). Alternatively, ferritin expression has been shown to be increased in the CSF and serum of SPMS patients (LeVine et al. 1999; Petzold et al. 2002; Sfagos et al. 2005; Worthington et al. 2010), and since ferritin has a large capacity to bind iron, it is possible that it is responsible for delivering extra iron to neurons since the H-ferritin receptor in humans is the transferrin receptor (Li et al. 2010) that is expressed by neurons (Chen-Roetling et al. 2011).

DMT1 (a.k.a., Nramp2, DCT1, and SLC11A2) is an energy dependent transporter found in the membrane that co-transports H+ and the ferrous iron from the endosome to the interior of the cell (Moos and Morgan 2004; Dunn et al. 2007; Richardson et al. 2010; Crichton et al. 2011). DMT1 has two isoforms, one with an IRE in its 3′ untranslated region and one without the IRE (Huang et al. 2006). The isoform with the IRE is regulated by the intracellular iron concentration, while the isoform without the IRE is regulated by inflammation (Mackenzie and Hediger 2004). This latter isoform has an interferon-γ responsive element, an AP-1 binding site, and an NF-κB binding site, making it susceptible to inflammatory regulation, e.g., upregulation in response to TNF-α (Huang et al. 2006). In addition, the DMT1 gene has a hypoxia response element that binds hypoxia-inducible factor-1 (Qian et al. 2011). If hypoxic conditions develop in MS as suggested (Aboul-Enein et al. 2003; Lassmann 2003; Mahad et al. 2008b, Trapp and Stys 2009; Cunnea et al. 2011), then the response by DMT1 and by the transferrin receptor (discussed above) could facilitate the cellular uptake of iron. Moreover, activation of the NMDA receptor is thought to induce a cascade of reactions, including signaling by nitric oxide, that promotes neuronal iron uptake by DMT1 (Cheah et al. 2006; Pelizzoni et al. 2011), although another study found decreased transcription of DMT1 in response to exogenous nitric oxide (Paradkar and Roth 2006).

Neuronal uptake of ferrous iron via DMT1 could lead to oxidative damage. For example in a model of PD, the exposure of a neuronal cell line to 1-methyl-4-phenylpyridinium (MPP+) resulted in increased intracellular iron concentration, and the influx of iron appeared to lead to mitochondrial membrane depolarization, increased ROS, and ultimately caspase-3 activation (Zhang et al. 2009). The uptake of the additional iron was due to the increased expression of the non-IRE containing DMT1 isoform; thus, DMT1 expression was driven by factors other than intracellular iron concentration (Zhang et al. 2009). In other models, DMT1 expression was upregulated for a sustained period, i.e., 2 months, in astrocytes following exposure to kainate (Huang et al. 2006), and glia accumulate iron within mitochondria following exposure to proinflammatory cytokines (Mehindate et al. 2001). In contrast, in a 6-hydroxydopamine model of PD it was the DMT1 isoform with the IRE that was upregulated (Jiang et al. 2010). Regardless of the method of enhanced uptake, the elevated iron has been postulated to contribute to oxidative stress in PD (Zhang et al. 2009; Jiang et al. 2010) and in other models of neurodegeneration (Cheah et al. 2006; Pelizzoni et al. 2011). In addition, oxidative damage to iron sensor proteins in mitochondria has been proposed to signal enhanced iron uptake in mitochondria within dopaminergic neurons via the transferrin/transferrin receptor 2 system (Mastroberardino et al. 2009).

Iron uptake in white matter and its relationship to MS

The cellular distribution of iron-enriched cells in white matter changes during brain development. At postnatal day 3, iron is enriched in vessels and in cells with a morphology consistent with ameboid microglia, but by postnatal day 14 the majority of iron enriched cells appear to be developing oligodendrocytes and by postnatal day 21 mature oligodendrocytes are enriched with iron (Connor et al. 1995). During development, the expression of the transferrin receptors also shifts; it is present in ameboid microglia, along vessels as well as on developing oligodendrocytes, but mature oligodendrocytes are devoid of transferrin receptors (Lin and Connor 1989; Kaur and Ling 1995, 1999; Hulet et al. 1999a). Although transferrin has been shown to be an important factor that promotes myelination (Espinosa-Jeffrey et al. 2002; Saleh et al. 2003; Badaracco et al. 2008) and remyelination (Adamo et al. 2006), other mechanisms also function to deliver iron to oligodendrocytes.

Microglia, which are enriched with iron during development, could be a source of iron for developing oligodendrocytes. Indeed, conditioned media from non-activated microglia enriched with iron promoted the survival and/or proliferation of oligodendrocytes, and heavy chain ferritin was identified as the component within the conditioned media responsible for this effect (Zhang et al. 2006). H-ferritin has been shown to bind white matter (Hulet et al. 1999a) with a temporal profile of binding that matches myelination (Hulet et al. 2002), and the expression of H-ferritin shifts from microglia to oligodendrocytes during this developmental period (Cheepsunthorn et al. 1998). H-ferritin binds receptors on oligodendrocyte precursors and then gets taken up via clathrin mediated endocytosis (Hulet et al. 2000). The uptake of H-ferritin results in an increase in the labile pool of iron within oligodendrocytes, which in turn causes a decrease in IRP/IRE binding and presumably decreased transferrin receptor expression, while the expression of the H-ferritin receptor in rodents is thought to be independent of IRE/IRP control (Hulet et al. 2000). The receptor for H-ferritin on rat oligodendrocytes is T cell immunoglobulin and mucin domain-containing protein-2 (Tim-2) (Todorich et al. 2008), and indeed, no standard IRE was found for Tim-2 (Han et al. 2011). However, Tim-2 is not expressed in humans (Kuchroo et al. 2003). Besides serving as a receptor for transferrin, the transferrin receptor-1 is also a receptor for H-ferritin in humans (Li et al. 2010) and it is present on neurons (Chen-Roetling et al. 2011). Due to the large binding capacity of iron by ferritin, H-ferritin is thought to serve as the major delivery vehicle for the elevated amounts of iron that are required by oligodendrocytes for myelination (Hulet et al. 2000; Todorich et al. 2011) and may contribute to neuronal iron uptake as well.

In MS tissue, receptors for H-ferritin were found in normal white matter but not in periplaque regions nor within the plaques, however, expression of the transferrin receptor was observed within the periplaque region and somewhat within the plaques (Hulet et al. 1999b). The plaques and periplaque region are areas that can contain remyelinating oligodendrocytes (Lucchinetti et al. 1999), which is consistent with the expression of the transferrin receptor observed within these areas since it is present on developing oligodendrocytes (Lin and Connor 1989; Hulet et al. 1999a). Tim-2, the receptor for H-ferritin on rat oligodendrocytes, is also present on Th2 cells in mice and it acts to negatively regulate T cell activity (Chakravarti et al. 2005; Knickelbein et al. 2006). Along these lines, H-ferritin acts as an immunosuppresent by inhibiting the proliferation of myeloid cells and mitogen activated T cells as well as decreasing the maturation of B cells (Recalcati et al. 2008) and apoferritin was found to attenuate disease activity in EAE (LeVine et al. 2002).

Iron is thought to have a key role in myelination due to its role as a cofactor in reactions involved in lipid biosynthesis and its role in mitochondrial function, both of which are highly active in myelinating oligodendocytes (Connor and Menzies 1996). However, the absence of iron histochemical staining in oligodendrocytes in some species (Erb et al. 1996), and the patchy staining of oligodendrocytes in white matter in the rat (Connor et al. 1995) indicate that enhanced levels of iron may not be essential for myelination and/or that histochemical detection may not reflect the actual distribution of iron (LeVine and Macklin 1990; LeVine 1991). Regardless, iron deficiency does lead to altered myelination (Algarín et al. 2003) and the iron status has been suggested to be associated with MS. For instance, there has been a report of two pediatric patients with iron deficiency that had tumefactive demyelination with presentations that advanced to satisfy the criteria of pediatric MS (van Toorn et al. 2010). Since recurring iron supplementation was required to alleviate this deficiency, it was suggested that an underlying cause was due to a mutation leading to altered iron uptake (van Toorn et al. 2010). Whether a deficiency in iron could impact the development and/or progression of pediatric MS is unclear, but both patients had low serum ferritin levels, presumably due to the iron deficient state, and since ferritin acts as an immunosuppressant (LeVine et al. 2002; Recalcati et al. 2008) it is possible that these low levels allowed for an enhanced level of immune activation to occur, and this contributed to the disease process. Thus, iron replenishment might help to suppress disease activity by promoting greater levels of ferritin in iron deficient patients. In contrast, a low iron diet has been shown to impair the ability of mice to develop EAE and it was proposed that the iron deficiency disrupted the development of T cells that are necessary for the disease process (Grant et al. 2003). Indeed, iron chelation inhibits the proliferation of stimulated mouse and human T cells and it has been shown to limit the progression of EAE disease activity (Mitchell et al. 2007; Sweeney et al. 2011). Iron chelation is thought to limit the availability of iron for ribonucleotide reductase (Cooper et al. 1996) which is used for DNA synthesis. Interfering with DNA synthesis induces cytostasis of T cells and B cells, and this strategy of inducing cytostasis is being tested in MS and rheumatoid arthritis patients although a different enzyme, dihydro-orotate dehydrogenase, is being inhibited by means other than chelation (Warnke et al. 2009).

Mechanisms of iron deposition along vessels in MS

Multiple studies have identified iron deposition along blood vessels in MS, but the mechanism for this deposition is under debate. One hypothesis proposed that an initial defect in the vessels themselves, i.e., stenosis of vessels in the chest or neck, leads to altered blood flow resulting in upstream perivenular iron deposition (Zamboni 2006; Zamboni et al. 2007; Singh and Zamboni 2009). It was suggested that the role of iron in chronic venous disorder (CVD) in the leg may parallel that in MS since perivenular iron deposits occur in both CVD and MS. In CVD, the transmural pressure across the wall of a vessel is increased as a result of venous stasis (Zamboni et al. 2008). The increased pressure is thought to lead to extravasation of erythrocytes through the fenestrated capillary walls into the interstitium. Once the erythrocytes reach the interstitial space, macrophages degrade the erythrocytes and release iron, which is stored in ferritin and/or develops into hemosiderin (Koeppen et al. 1995; Zamboni et al. 2005; Zamboni 2006). However, the mechanism for iron deposition along vessels in the brain may be more complicated since the intact or partially disrupted BBB would serve to prevent the extravasation of erythrocytes that otherwise might occur through fenestrated capillaries as a result of an increase in transmural pressure. Furthermore, the notion that vessel stenosis is a causative feature connected with MS has been challenged (Doepp et al. 2010; Sundstrom et al. 2010; Auriel et al. 2011; Marder et al. 2011).

Vessel associated changes do occur in the CNS of MS and EAE subjects, but these changes are secondary events to other pathological occurrences. For instance, vessel alterations can be induced as a consequence of an overall autoimmune response directed to myelin antigens (McFarland and Martin 2007). This response includes the trafficking of immune cells (e.g., T cells, B cells, macrophages) from the blood into the CNS and damage to the BBB (Trebst et al. 2003; Cassan and Liblau 2007). A breach in the BBB can result in the extravasation of RBCs into the CNS (Adams 1988, 1989; Adams et al. 1989; Forge et al. 1998) which could be a source of both recent and long standing iron deposits around vessels in MS subjects (Adams 1988, 1989). However, iron deposits along vessels can also occur independent of extravasated RBCs (Forge et al. 1998; Pedchenko and LeVine 1998; Williams et al. 2011).

Vessel associated iron deposition can also occur in response to enhanced demand for iron in the CNS. As mentioned earlier, there can be an enhanced metabolic demand put on neurons in response to a variety of stresses associated with MS. Vessels can respond to inflammatory stress by upregulating the expression of hypoxia-inducible factor, which in turn causes the upregulation of transferrin receptor (Lok and Ponka 1999; Omori et al. 2003). Thus, vessel associated iron due to this upregulation would not necessarily be restricted to sites of inflammatory cell infiltration, but rather could occur throughout the CNS. Support for this idea is found in the twitcher model of Krabbe disease (globoid cell leukodystrophy), which is due to a mutation in galactosylceramidase whose normal function is to breakdown glactosylceramide and psychosine. In this disease there is extensive demyelination throughout the CNS, infiltration of macrophages predominantly in white matter tracks, and elevated levels of inflammatory mediators, e.g., TNF-α and IL-6 (LeVine and Brown 1997; Biswas et al. 2002). Iron deposits are found on veins throughout the CNS even though these vessels are not directly associated with macrophage infiltration into the CNS (LeVine and Torres 1992). The elevated level of iron deposition along vessels in twitcher mice is hypothesized to be in response to the ongoing inflammatory milieu which would have similarities to that which occurs in MS and EAE, e.g., elevated levels of pro-inflammatory cytokines, CNS infiltration of macrophages, and demyelination.

The reduction of blood flow could restrict the delivery of oxygen to MS patients (Lassmann 2003; Law et al. 2004; Ge et al. 2005, 2009; Inglese et al. 2007; Zamboni et al. 2007) resulting in a hypoxic state (Aboul-Enein et al. 2003; Lassmann 2003; Mahad et al. 2008b, Trapp and Stys 2009; Cunnea et al. 2011). Hypoxia leads to upregulation of hypoxia inducible factor-1α which in turn results in increased expression of vascular endothelial growth factor (VEGF) in astrocytes (Sinor et al. 1998; Kaur et al. 2006; Kaur and Ling 2008). VEGF enhances BBB leakage and induces angiogenesis (Zhang et al. 2000; Kaur and Ling 2008). VEGF is expressed by astrocytes in MS white matter lesions (Proescholdt et al. 2002; Seabrook et al. 2010) but was not detected in white matter from control subjects (Seabrook et al. 2010). VEGF expression is also increased in EAE subjects (Proescholdt et al. 2002; Roscoe et al. 2009). Thus, VEGF could facilitate BBB leakage, which is present in both EAE and MS. Vessel numbers are also increased in EAE (Roscoe et al. 2009; Seabrook et al. 2010) and MS (Holley et al. 2010) subjects compared to control subjects and VEGF may protect neurons against excitotoxic injury and other types of neuroal stress (Ruiz de Almodovar et al. 2009; Tovar-Y-Romo and Tapia, 2010). Thus, VEGF could also have a beneficial role by compensating for an ischemic state by generating more vessels and protecting neurons. Of note, iron chelation which has been examined in EAE and MS (Bowern et al. 1984; Norstrand and Craelius 1989; Lynch et al. 1996, 2000; Pedchenko and LeVine, 1998; Mitchell et al. 2007) can cause a hypoxia like state to the microvasculature (Bartolome et al. 2009) resulting in an induction of VEGF expression (Hodges et al. 2005; Chi et al. 2008; Kupershmidt et al. 2011). Thus, iron chelation could impact disease activity via upregulation of VEGF.

Recently, IRPs have been identified in the choroid plexus and microvasculature of the brain (Connor et al. 2011). Since the transferrin receptor has an IRE (Wang and Pantopoulos 2011) and is expressed by brain endothelial cells (Piñero and Connor 2000), it indicates that regulation of iron entry into the brain can be controlled at the BBB (Connor et al. 2011). DMT1, which also has an IRE, has been detected within the rat brain endothelium (Burdo et al. 2001, 2003) and it transports iron from the endosome to the cytoplasm (Moos and Morgan 2004; Dunn et al. 2007; Richardson et al. 2010; Crichton et al. 2011). Furthermore, ferritin has been detected in the microvasculature indicating that iron can be stored at the BBB (Connor et al. 2011). Dysregulation of the IRP/IRE regulatory system leading to enhanced iron storage could facilitate the deposition of iron in vessels of MS brains.

Mechanisms of iron deposition in microglia/macrophages in MS

Activated microglial cells have been linked to neuronal damage, cortical lesions, and loss of neuronal processes in MS (Kutzelnigg and Lassmann 2005; Dutta and Trapp 2007; Vercellino et al. 2007). Interestingly, iron enriched macrophages are often associated with vessels in MS and pathological iron deposits have been demonstrated within activated microglia and macrophages (Craelius et al. 1982; Adams 1988, 1989; LeVine 1997; Zamboni 2006; Singh and Zamboni 2009; Williams et al. 2011) and these cells express ferritin (Kaneko et al. 1989; Chi et al. 2000). It is likely that these cells phagocytose extravasated RBCs upon entering the CNS. Upregulation of transferrin receptor expression and enhanced iron uptake occur in ameboid microglia in response to hypoxia in developing rats (Kaur and Ling 1995, 1999) and in macrophages in response to inflammatory stimuli (Tacchini et al. 2008). In the latter example, increased transferrin expression is mediated through increased transcription via NF-κB activation of hypoxia inducible factor-1 (Tacchini et al. 2008), and it is possible that similar mechanisms could function in MS. It is also plausible that the macrophages contained high levels of iron prior to emigration to the CNS (Williams et al. 2011), since macrophages are known to sequester iron or limit its release during inflammation (Knutson and Wessling-Resnick 2003; Tacchini et al. 2008), which is thought to be a mechanism of reducing extracellular iron availability to bacteria (Ganz 2009).

In addition, macrophages and microglia may acquire high levels of iron by phagocytosing myelin/oligodendrocyte debris. During normal conditions, iron is enriched within the cytoplasm of oligodendrocytes and within the inner and outer loops of myelin (Rajan et al. 1976; Francois et al. 1981; Hill and Switzer 1984; Hill et al. 1985; Dwork et al. 1988; Gerber and Connor 1989; Connor and Menzies 1990; Connor et al. 1990; LeVine and Macklin 1990; LeVine 1991). This high level of iron may be due to the abundance of iron-containing biosynthetic enzymes that are used to meet the high metabolic demands of myelinogenesis (LeVine and Macklin 1990; Connor et al. 1995; LeVine and Chakrabarty 2004). During EAE and MS, macrophages are actively associated with demyelinating lesions, and as the myelin/oligodendrocyte debris is phagocytosed the iron concentration within macrophages would increase.

Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1 (Slc11a1), which was formerly known as Nramp1, is a late endosomal/lysosomal integral membrane protein present in granulocytes and macrophages (Huynh and Andrews 2008; Taylor and Kelly 2010). It acts to pump divalent cations out of the phagolysosome and acid in. This action moves iron into the cytoplasm and depletes iron within the phagolysosome thereby depriving intracellular pathogenes of iron which is necessary for their growth (Huynh and Andrews 2008; Taylor and Kelly 2010). Alleles of Slc11a1 have been linked to autoimmune disorders (Bowlus 2003). This raises the possibility that iron metabolism is involved with the autoimmune process, perhaps by affecting epitope exposure via iron catalyzed reactive species (Bowlus 2003). However, genetic studies examining the relationship of Nramp1 alleles relative to MS have yielded conflicting results. Two studies suggest a linkage between alleles of Nramp1 and MS (Kotze et al. 2001; Gazouli et al. 2008) while two other studies have failed to detect an association (Comabella et al. 2004; Ates et al. 2010). Thus, further study is required to clarify whether an association between Slc11a1 and MS exists.

Effects of enhanced intracellular iron concentrations on glia

Iron concentrations can affect macrophage/microglial function by enhancing their release of inflammatory molecules. For instance, lipopolysaccharide (LPS)-activated microglia that were loaded with iron had increased release of matrix metalloproteinases-9 (MMP-9) (Mairuae et al. 2011) and the proinflammatory cytokines TNF-α and IL-1β (Zhang et al. 2006) as compared to non-iron loaded LPS-activated microglial cells. MMP-9 levels are increased in the serum (Liuzzi et al. 2002) and CSF (Leppert et al. 1998) of MS subjects, and MMP-9 is expressed by microglial nodules, macrophages and some astrocytes in MS brains (Maeda and Sobel 1996). Interestingly, iron deficiency may also lead to enhanced MMP-9 in macrophages (Fan et al. 2011). MMP-9 activity is thought to be involved in the breakdown of the BBB that occurs in MS and may facilitate epitope spreading through proteolytic cleavage of myelin proteins (Ram et al. 2006).

Culture media from activated microglial cells, iron loaded or non-loaded, was toxic to oligodendrocytes, and iron chelation reversed the toxicity of the conditioned media from non-iron loaded activated microglia (Zhang et al. 2006). Iron also has the potential to enhance the effector functions of microglial cells as demonstrated by the ability of iron treated microglial cells to dispense of Candida albicans (Saleppico et al. 1996). Macrophages are also susceptible to changes in iron concentrations, i.e., increases in iron lead to the activation of NF-κB and an increase in ROS and cytokine production (Crichton et al. 2002; Sindrilaru et al. 2011). Furthermore, iron-catalyzed ROS may expose cryptic epitopes, oxidatively modify proteins or generate unique peptide fragments that could undergo antigen presentation in autoimmune diseases (Casciola-Rosen et al. 1997; Kalluri et al. 2000; Trigwell et al. 2001). Thus, increased iron concentrations in macrophages/microglia are positioned to exacerbate EAE and MS pathogenesis.

When cultured oligodendrocyte precursors were enriched with iron using 3,5,5-trimethylhexanoyl (TMH)-ferrocene, they were more sensitive to death in the presence of proinflammatory cytokines compared to non-iron enriched precursors (Zhang et al. 2005). The enhanced toxicity was thought to include mitochondrial dysfunction, i.e., a decreased mitochondrial membrane potential, and enhanced oxidative stress, i.e., increased lipid peroxidation (Zhang et al. 2005). In astrocytes, survival and mitochondrial function were more sensitive to oxidative stress when these cells were preloaded with the lipophilic TMH-ferrocene iron compound (Robb and Connor 1998; Robb et al. 1999) although these cells were more resistant to the effects of iron than were oligodendrocytes (Zhang et al. 2005). Thus, oligodendrocytes which typically have high concentrations of iron are potentially sensitive to the pro-oxidative environment that can occur in MS.

Iron and neurodegeneration

Axonal injury leading to transection and neuronal stress leading to neurodegeneration are two mechanisms that can have profound implications for functional deficits in MS subjects. Axonal injury and/or transection are thought to begin early in the disease course (Bjartmar and Trapp 2001; De Stefano et al. 2001), and in acute or focal white matter lesions they are related to inflammation resulting in the production of a large variety of toxic substances including reactive oxygen species and MMPs (Trapp et al. 1998, 1999; Dutta and Trapp 2011). However, pathogenic mechanisms that promote axonal degeneration (Trapp et al. 1999; Bjartmar and Trapp 2001; Dutta and Trapp 2011) and neurite and neuronal loss (Peterson et al. 2001; Vercellino et al. 2005; Dutta and Trapp 2007) can occur in addition to or in the absence of obvious cellular inflammation or ongoing demyelination. Possible mechanisms include mitochondrial dysfunction, excitotoxicity (e.g., excessive glutamate), microglial activation, loss of trophic support (e.g., myelin itself provides trophic support for axons, thus, demyelination reduces this support), and energy imbalance tied to channel redistributions and channel dysfunction (Trapp et al. 1999; Dutta and Trapp 2007, 2011). Interestingly, iron might have a contributory role to one or more of these mechanisms.

Deep gray matter structures are important sites of neurodegeneration in MS subjects (Vercellino et al. 2009) and these regions are where substantial iron deposition occurs (Drayer et al. 1987a,b; Grimaud et al. 1995; Russo et al. 1997; Bakshi et al. 2000; Ge et al. 2007; Haacke et al. 2009, 2010a; Khalil et al. 2009). Iron deposits are also observed in Alzheimer disease (AD) and PD at sites of neurodegeneration (Sayre et al. 2005; Berg and Youdim 2006; Carbonell and Rama 2007) suggesting that the role of iron in neurodegeneration in MS may share similarities to its role in neurodegeneration in other neurological diseases. As mentioned earlier, iron amplifies the activated state of macrophages/microglia, and these activated cells can negatively impact neurons (Takeuchi et al. 2005; Bartnik et al. 2000; Roediger and Armati 2003; Brown and Neher 2010; Centonze et al. 2010). Iron has been shown to promote glutamate release by neuronal, retinal pigment epithelial and lens epithelial cells (McGahan et al. 2005) and iron promotes the neurotoxic effects of glutamate (Yu et al. 2009).

Several studies have demonstrated that mitochondria are dysfunctional in MS (Mahad et al. 2008a; Mao and Reddy 2010) as well as in other neurological diseases such as AD and PD (Gille and Reichmann 2011; Lassmann 2011). This dysfunction could be related to the reduction of blood flow in the cerebrum of MS patients resulting in reduced oxygen availability (Lassmann 2003; Law et al. 2004; Ge et al. 2005, 2009; Inglese et al. 2007; Zamboni et al. 2007). The reduced oxygen supply negatively impacts cerebral metabolism and adds an additional stress to mitochondria that are trying to meet an aerobic set point (Bakshi et al. 1998; Mahad et al. 2008a; Mao and Reddy 2010). This stress could allow mitochondria to become dysfunctional resulting in excess production of ROS (Mahad et al. 2008a; Mao and Reddy 2010). In an attempt to achieve a normal level of function, the mitochondria may undergo biogenesis, thereby increasing the amount of dysfunctional ROS-producing mitochondria (Onyango et al. 2010). This would also increase the amount of intracellular iron, which would be required by the additional mitochondrial enzymes. Elevated levels of iron together with increased ROS production from dysfunctional mitochondria have the potential to create a sustained pro-oxidative intracellular environment that ultimately leads to neuronal degeneration (Deng et al. 2010; Pelizzoni et al. 2011).

In the presence of excess iron, the production of ROS can increase via iron catalyzed reactions. ROS can negatively impact mitochondrial function and lead to oxidative damage of lipids, proteins, and nucleic acids. Evidence of ROS induced oxidative damage can be seen in the EAE models and in MS patients by decreased levels of glutathione, a key component of one of the body’s natural antioxidant systems (Honegger et al. 1989; Calabrese et al. 2003; Chakrabarty et al. 2003; Srinivasan et al. 2010; Choi et al. 2011). Additionally, lipid peroxidation byproducts and increased ROS production from inflammatory cells occur in EAE and MS (Hammann and Hopf 1986; Fisher et al. 1988; Honegger et al. 1989; Langemann et al. 1992; MacMicking et al. 1992; Brett and Rumsby 1993; Ruuls et al. 1995; LeVine and Wetzel 1998; Penkowa et al. 2001; Calabrese et al. 2003; Ferretti et al. 2006). Iron also inhibits enzymatic function of base excision repair pathway for DNA damage and delayed the repair of oxidative damage to DNA in cultured neurons (Li et al. 2009). Thus, neuronal damage could occur from a combination of pro-oxidative conditions and inhibition of repair mechanisms.

Glutamate mediated toxicity

Glutamate excitotoxicity may be an important mechanism of injury to a variety of cell types in MS. Aside from neurons, NMDA receptors are expressed by oligodendrocytes (Wong 2006) and glutatmate excitotoxicity mediates oligodendrocyte cell death (Matute et al., 1997, 2011). In the MS brain glutamate levels are increased above normal levels and glutaminase is expressed by microglia and macrophages (Werner et al. 2001; Srinivasan et al. 2005; Bolton and Paul 2006). Increased glutamate release by monocytes and microglia in MS could be through the upregulation of the cystine/glutamate antiporter (Pampliega et al., 2011) which could be an integral step for glutamate-mediated toxicity to oligodendrocytes (Domercq et al. 2007). NMDA receptors are also present on brain endothelial cells and glutamate promotes barrier leakage through the NMDA receptor (Sharp et al. 2003). Furthermore, oxidative stress was shown to be involved with the barrier dysfunction due to NMDA activation and iron chelation was found to lessen the oxidative stress (Sharp et al. 2005). Glutamate excitotoxicty may promote iron uptake in rat spinal cord explants and iron may mediate neurotoxic effects of glutamate (Yu et al. 2009). Iron is tied to glutamate release by neuronal, retinal pigment epithelial and lens epithelial cells by increasing aconitase activity, which is utilized in the synthesis of precursors for glutamate (McGahan et al. 2005). The cystine/glutamate antiporter releases glutamate in exchange for cystine (Lall et al., 2008). Cystine is used in the synthesis of glutathione which is an important antioxidant, thus, iron could also indirectly promote protection against iron catalyzed oxidation in some cell types (Lall et al., 2008) but this role in cells relevant to MS is not established. Taken together, the interrelationship of iron status to glutamate excitotoxicity mediated cellular damage might be relevant to MS pathogenesis but more investigations are required.


Iron abnormally accumulates in the CNS of MS patients along vessels and in deep gray matter structures (Fig. 1). The accumulation of iron and its role in pathogenesis may differ among CNS regions and/or among the various forms of MS. The presence of excess iron has the potential to induce negative consequences such as promoting oxidative stress, blocking repair mechanisms, activating microglia and macrophages to enhance their production of proinflammatory mediators, and/or facilitating mitochondrial changes leading to cellular degeneration (Fig. 1). Identifying the relative contributions of iron deposition to MS pathogenic mechanisms through further study will help to determine whether therapeutic interventions should target iron, e.g., limit its accumulation, promote its removal, block its toxic activity and/or ameliorate its downstream pathogenic effects.

Figure 1
Mechanisms of iron uptake and iron induced toxicity that have potential relevance for MS pathogenesis. Uptake of iron by oligodendrocytes changes with development. Initially, transferrin is thought to deliver iron via the transferrin receptor in developing ...


This work was supported by a research grants from the National Multiple Sclerosis Society (NMSS), Heartland Border Walk for MS (HBWMS), and a center grant NICHD HD002528. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NMSS, HBWMS and NICHD.

Abbreviations used

Alzheimer disease
blood-brain barrier
central nervous system
cerebrospinal fluid
chronic venous disorder
divalent metal transporter 1
experimental autoimmune encephalomyelitis
iron regulatory element
iron regulatory proteins
magnetic field correlation
multiple sclerosis
Parkinson disease
red blood cells
reactive oxygen species
relapsing remitting multiple sclerosis
secondary progressive multiple sclerosis
susceptibility weighted imaging
tumor necrosis factor-α
vascular endothelial growth factor


The authors declare no conflict of interest.


  • Abo-Krysha N, Rashed L. The role of iron dysregulation in the pathogenesis of multiple sclerosis: an Egyptian study. Mult Scler. 2008;14:602–608. [PubMed]
  • Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Bruck W, Lucchinetti C, Schmidbauer M, Jellinger K, Lassmann H. Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropathol Exp Neurol. 2003;62:25–33. [PubMed]
  • Adamo AM, Paez PM, Escobar Cabrera OE, Wolfson M, Franco PG, Pasquini JM, Soto EF. Remyelination after cuprizone-induced demyelination in the rat is stimulated by apotransferrin. Exp Neurol. 2006;198:519–529. [PubMed]
  • Adams CW. Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1988;51:260–265. [PMC free article] [PubMed]
  • Adams CW. A Color Atlas of Multiple Sclerosis and Other Myelin Disorders. Wolfe Medical Publication; London: 1989. Vascular aspects of multiple sclerosis.
  • Adams CW, Poston RN, Buk SJ. Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J Neurol Sci. 1989;92:291–306. [PubMed]
  • Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 1990;13:266–271. [PubMed]
  • Algarín C, Peirano P, Garrido M, Pizarro F, Lozoff B. Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr Res. 2003;53:217–223. [PubMed]
  • Andrews H, White K, Thomson C, Edgar J, Bates D, Griffiths I, Turnbull D, Nichols P. Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J Neurosci Res. 2006;83:1533–1539. [PubMed]
  • Ates O, Kurt S, Bozkurt N, Karaer H. NRAMP1(SLC11A1) variants: genetic susceptibility to multiple Sclerosis. J Clin Immunol. 2010;30:583–586. [PubMed]
  • Auriel E, Karni A, Bornstein NM, Nissel T, Gadoth A, Hallevi H. Extra-cranial venous flow in patients with multiple sclerosis. J Neurol Sci 2011 [PubMed]
  • Badaracco ME, Ortiz EH, Soto EF, Connor J, Pasquini JM. Effect of transferrin on hypomyelination induced by iron deficiency. J Neurosci Res. 2008;86:2663–2673. [PubMed]
  • Baeten K, Hendriks JJ, Hellings N, Theunissen E, Vanderlocht J, Ryck LD, Gelan J, Stinissen P, Adriaensens P. Visualisation of the kinetics of macrophage infiltration during experimental autoimmune encephalomyelitis by magnetic resonance imaging. J Neuroimmunol. 2008;195:1–6. [PubMed]
  • Bakshi R, Benedict RH, Bermel RA, Caruthers SD, Puli SR, Tjoa CW, Fabiano AJ, Jacobs L. T2 hypointensity in the deep gray matter of patients with multiple sclerosis, a quantitative magnetic resonance imaging study. Arch Neurol. 2002;59:62–68. [PubMed]
  • Bakshi R, Miletich RS, Kinkel PR, Emmet ML, Kinkel WR. High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging. 1998;8:228–234. [PubMed]
  • Bakshi R, Shaikh ZA, Janardhan V. MRI T2 shortening (‘black T2’) in multiple sclerosis: frequency, location, and clinical correlation. Neuroreport. 2000;11:15–21. [PubMed]
  • Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM. Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem. 1992;267:18148–18153. [PubMed]
  • Barbeito AG, Garringer HJ, Baraibar MA, Gao X, Arredondo M, Nunez MT, Smith MA, Ghetti B, Vidal R. Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. J Neurochem. 2009;109:1067–1078. [PMC free article] [PubMed]
  • Bartnik BL, Juurlink BH, Devon RM. Macrophages: their myelinotrophic or neurotoxic actions depend upon tissue oxidative stress. Mult Scler. 2000;6:37–42. [PubMed]
  • Bartolome S, Dhillon NK, Buch S, Casillan AJ, Wood JG, O’Brien-Ladner AR. Deferoxamine mimics the pattern of hypoxia-related injury at the microvasculature. Shock. 2009;31:481–485. [PubMed]
  • Berg D, Youdim MB. Role of iron in neurodegenerative disorders. Top Magn Reson Imaging. 2006;17:5–17. [PubMed]
  • Bermel RA, Puli SR, Rudick RA, Weinstock-Guttman B, Fisher E, Munschauer FE, 3rd, Bakshi R. Prediction of longitudinal brain atrophy in multiple sclerosis by gray matter magnetic resonance imaging T2 hypointensity. Arch Neurol. 2005;62:1371–1376. [PMC free article] [PubMed]
  • Bertoni-Freddari C, Fattoretti P, Casoli T, Di Stefano G, Solazzi M, Perna E, De Angelis C. Reactive structural dynamics of synaptic mitochondria in ischemic delayed neuronal death. Ann N Y Acad Sci. 2006;1090:26–34. [PubMed]
  • Bianchi L, Tacchini L, Cairo G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res. 1999;27:4223–4227. [PMC free article] [PubMed]
  • Biswas S, Biesiada H, Williams TD, LeVine SM. Delayed clinical and pathological signs in twitcher (globoid cell leukodystrophy) mice on a C57BL/6 x CAST/Ei background. Neurobiol Dis. 2002;10:344–357. [PubMed]
  • Bjartmar C, Trapp BD. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol. 2001;14:271–278. [PubMed]
  • Blinkenberg M, Jensen CV, Holm S, Paulson OB, Sorensen PS. A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS. Neurology. 1999;53:149–153. [PubMed]
  • Bolton C, Paul C. Glutamate receptors in neuroinflammatory demyelinating disease. Mediators Inflamm. 2006:93684. [PMC free article] [PubMed]
  • Boretius S, Schmelting B, Watanabe T, Merkler D, Tammer R, Czeh B, Michaelis T, Frahm J, Fuchs E. Monitoring of EAE onset and progression in the common marmoset monkey by sequential high-resolution 3D MRI. NMR Biomed. 2006;19:41–49. [PubMed]
  • Bowern N, Ramshaw IA, Clark IA, Doherty PC. Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent. J Exp Med. 1984;160:1532–1543. [PMC free article] [PubMed]
  • Bowlus CL. The role of iron in T cell development and autoimmunity. Autoimmun Rev. 2003;2:73–78. [PubMed]
  • Brass SD, Benedict RH, Weinstock-Guttman B, Munschauer F, Bakshi R. Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis. Mult Scler. 2006a;12:437–444. [PubMed]
  • Brass SD, Chen NK, Mulkern RV, Bakshi R. Magnetic resonance imaging of iron deposition in neurological disorders. Top Magn Reson Imaging. 2006b;17:31–40. [PubMed]
  • Brett R, Rumsby MG. Evidence of free radical damage in the central nervous system of guinea-pigs at the prolonged acute and early relapse stages of chronic relapsing experimental allergic encephalomyelitis. Neurochem Int. 1993;23:35–44. [PubMed]
  • Brochet B, Deloire MS, Touil T, Anne O, Caille JM, Dousset V, Petry KG. Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE. Neuroimage. 2006;32:266–274. [PubMed]
  • Brown GC, Neher JJ. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol. 2010;41:242–247. [PubMed]
  • Burdo JR, Antonetti DA, Wolpert EB, Connor JR. Mechanisms and regulation of transferrin and iron transport in a model blood–brain barrier system. Neuroscience. 2003;121:883–890. [PubMed]
  • Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR. Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res. 2001;66:1198–1207. [PubMed]
  • Calabrese V, Scapagnini G, Ravagna A, Bella R, Butterfield DA, Calvani M, Pennisi G, Giuffrida Stella AM. Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine. Neurochem Res. 2003;28:1321–1328. [PubMed]
  • Carbonell T, Rama R. Iron, oxidative stress and early neurological deterioration in ischemic stroke. Curr Med Chem. 2007;14:857–874. [PubMed]
  • Casciola-Rosen L, Wigley F, Rosen A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J Exp Med. 1997;185:71–79. [PMC free article] [PubMed]
  • Cassan C, Liblau RS. Immune tolerance and control of CNS autoimmunity: from animal models to MS patients. J Neurochem. 2007;100:883–892. [PubMed]
  • Ceccarelli A, Filippi M, Neema M, Arora A, Valsasina P, Rocca MA, Healy BC, Bakshi R. T2 hypointensity in the deep gray matter of patients with benign multiple sclerosis. Mult Scler. 2009;15:678–686. [PubMed]
  • Ceccarelli A, Rocca MA, Neema M, Martinelli V, Arora A, Tauhid S, Ghezzi A, Comi G, Bakshi R, Filippi M. Deep gray matter T2 hypointensity is present in patients with clinically isolated syndromes suggestive of multiple sclerosis. Mult Scler. 2010;16:39–44. [PubMed]
  • Ceccarelli A, Rocca MA, Perego E, Moiola L, Ghezzi A, Martinelli V, Comi G, Filippi M. Deep grey matter T2 hypo-intensity in patients with paediatric multiple sclerosis. Mult Scler. 2011 In press. [PubMed]
  • Centonze D, Muzio L, Rossi S, Furlan R, Bernardi G, Martino G. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ. 2010;17:1083–1091. [PubMed]
  • Chakrabarty A, Emerson MR, LeVine SM. Heme oxygenase-1 in SJL mice with experimental allergic encephalomyelitis. Mult Scler. 2003;9:372–381. [PubMed]
  • Chakravarti S, Sabatos CA, Xiao S, Illes Z, Cha EK, Sobel RA, Zheng XX, Strom TB, Kuchroo VK. Tim-2 regulates T helper type 2 responses and autoimmunity. J Exp Med. 2005;202:437–444. [PMC free article] [PubMed]
  • Cheepsunthorn P, Palmer C, Connor JR. Cellular distribution of ferritin subunits in postnatal rat brain. J Comp Neurol. 1998;400:73–86. [PubMed]
  • Cheah JH, Kim SF, Hester LD, Clancy KW, Patterson SE, 3rd, Papadopoulos V, Snyder SH. NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron. 2006;51:431–440. [PMC free article] [PubMed]
  • Chen-Roetling J, Chen L, Regan RF. Apotransferrin protects cortical neurons from hemoglobin toxicity. Neuropharmacology. 2011;60:423–431. [PMC free article] [PubMed]
  • Chi OZ, Hunter C, Liu X, Weiss HR. Effects of deferoxamine on blood-brain barrier disruption and VEGF in focal cerebral ischemia. Neurol Res. 2008;30:288–293. [PubMed]
  • Chi SI, Wang CK, Chen JJ, Chau LY, Lin TN. Differential regulation of H-and L-ferritin messenger RNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. Neuroscience. 2000;100:475–484. [PubMed]
  • Chin CL, Pai M, Bousquet PF, Schwartz AJ, O’Connor EM, Nelson CM, Hradil VP, Cox BF, McRae BL, Fox GB. Distinct spatiotemporal pattern of CNS lesions revealed by USPIO-enhanced MRI in MOG-induced EAE rats implicates the involvement of spino-olivocerebellar pathways. J Neuroimmunol. 2009;211:49–55. [PubMed]
  • Choi IY, Lee SP, Denney DR, Lynch SG. Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Mult Scler. 2011;17:289–296. [PMC free article] [PubMed]
  • Ciccarelli O, Altmann DR, McLean MA, Wheeler-Kingshott CA, Wimpey K, Miller DH, Thompson AJ. Spinal cord repair in MS: does mitochondrial metabolism play a role? Neurology. 2010;74:721–727. [PMC free article] [PubMed]
  • Connor JR, Menzies SL. Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience. 1990;34:265–271. [PubMed]
  • Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. Glia. 1996;17:83–93. [PubMed]
  • Connor JR, Menzies SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990;27:595–611. [PubMed]
  • Connor JR, Pavlick G, Karli D, Menzies SL, Palmer C. A histochemical study of iron-positive cells in the developing rat brain. J Comp Neurol. 1995;355:111–123. [PubMed]
  • Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain. 2011;134:959–968. [PMC free article] [PubMed]
  • Comabella M, Altet L, Peris F, Villoslada P, Sánchez A, Montalban X. Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients. Mult Scler. 2004;10:618–620. [PubMed]
  • Cooper CE, Lynagh GR, Hoyes KP, Hider RC, Cammack R, Porter JB. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J Biol Chem. 1996;271:20291–20299. [PubMed]
  • Craelius W, Migdal MW, Luessenhop CP, Sugar A, Mihalakis I. Iron deposits surrounding multiple sclerosis plaques. Arch Pathol Lab Med. 1982;106:397–399. [PubMed]
  • Crichton RR, Dexter DT, Ward RJ. Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm. 2011;118:301–314. [PubMed]
  • Crichton RR, Wilmet S, Legssyer R, Ward RJ. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem. 2002;91:9–18. [PubMed]
  • Crompton DE, Chinnery PF, Fey C, Curtis AR, Morris CM, Kierstan J, Burt A, Young F, Coulthard A, Curtis A, Ince PG, Bates D, Jackson MJ, Burn J. Neuroferritinopathy: a window on the role of iron in neurodegeneration. Blood Cells Mol Dis. 2002;29:522–531. [PubMed]
  • Cunnea P, Ni Mhaille A, McQuaid S, Farrell M, McMahon J, Fitzgerald U. Expression profiles of endoplasmic reticulum stress-related molecules in demyelinating lesions and multiple sclerosis. Mult Scler. 2011 In press. [PubMed]
  • Deng X, Vidal R, Englander EW. Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy. Neurosci Lett. 2010;479:44–48. [PMC free article] [PubMed]
  • De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol. 2001;58:65–70. [PubMed]
  • Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010;68:173–183. [PubMed]
  • Domercq M, Sánchez-Gómez MV, Sherwin C, Etxebarria E, Fern R, Matute C. System xc-and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J Immunol. 2007;178:6549–6556. [PubMed]
  • Dousset V, Ballarino L, Delalande C, Coussemacq M, Canioni P, Petry KG, Caille JM. Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis. AJNR Am J Neuroradiol. 1999;20:223–227. [PubMed]
  • Drayer B, Burger P, Hurwitz B, Dawson D, Cain J. Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: increased iron content? AJR Am J Roentgenol. 1987a;149:357–363. [PubMed]
  • Drayer BP, Burger P, Hurwitz B, Dawson D, Cain J, Leong J, Herfkens R, Johnson GA. Magnetic resonance imaging in multiple sclerosis: decreased signal in thalamus and putamen. Ann Neurol. 1987b;22:546–550. [PubMed]
  • Dunn LL, Rahmanto YS, Richardson DR. Iron uptake and metabolism in the new millennium. Trends. Cell Biol. 2007;17:93–100. [PubMed]
  • Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology. 2007;68:S22–S31. [PubMed]
  • Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011;93:1–12. [PMC free article] [PubMed]
  • Dwork AJ, Schon EA, Herbert J. Nonidentical distribution of transferrin and ferric iron in human brain. Neuroscience. 1988;27:333–345. [PubMed]
  • Erb GL, Osterbur DL, LeVine SM. The distribution of iron in the brain: a phylogenetic analysis using iron histochemistry. Brain Res Dev Brain Res. 1996;93:120–128. [PubMed]
  • Espinosa-Jeffrey A, Kumar S, Zhao PM, Awosika O, Agbo C, Huang A, Chang R, De Vellis J. Transferrin regulates transcription of the MBP gene and its action synergizes with IGF-1 to enhance myelinogenesis in the md rat. Dev Neurosci. 2002;24:227–241. [PubMed]
  • Fan Y, Wang J, Wei L, He B, Wang C, Wang B. Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-kappaB pathway. Int J Cardiol. 2011;152:49–55. [PubMed]
  • Ferretti G, Bacchetti T, DiLudovico F, Viti B, Angeleri VA, Danni M, Provinciali L. Intracellular oxidative activity and respiratory burst of leukocytes isolated from multiple sclerosis patients. Neurochem Int. 2006;48:87–92. [PubMed]
  • Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR. Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol. 2007;293:C641–C649. [PubMed]
  • Fisher M, Levine PH, Weiner BH, Vaudreuil CH, Natale A, Johnson MH, Hoogasian JJ. Monocyte and polymorphonuclear leukocyte toxic oxygen metabolite production in multiple sclerosis. Inflammation. 1988;12:123–131. [PubMed]
  • Floris S, Blezer EL, Schreibelt G, Dopp E, van der Pol SM, Schadee-Eestermans IL, Nicolay K, Dijkstra CD, de Vries HE. Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain. 2004;127:616–627. [PubMed]
  • Forge JK, Pedchenko TV, LeVine SM. Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis. Life Sci. 1998;63:2271–2284. [PubMed]
  • Francois C, Nguyen-Legros J, Percheron G. Topographical and cytological localization of iron in rat and monkey brains. Brain Res. 1981;215:317–322. [PubMed]
  • Gaasch JA, Geldenhuys WJ, Lockman PR, Allen DD, Van der Schyf CJ. Voltage-gated calcium channels provide an alternate route for iron uptake in neuronal cell cultures. Neurochem Res. 2007;32:1686–1693. [PubMed]
  • Ganz T. Iron in innate immunity: starve the invaders. Curr Opin Immunol. 2009;21:63–67. [PMC free article] [PubMed]
  • Gazouli M, Sechi L, Paccagnini D, Sotgiu S, Arru G, Nasioulas G, Vassilopoulos D. NRAMP1 polymorphism and viral factors in Sardinian multiple sclerosis patients. Can J Neurol Sci. 2008;35:491–494. [PubMed]
  • Ge Y, Jensen JH, Lu H, Helpern JA, Miles L, Inglese M, Babb JS, Herbert J, Grossman RI. Quantitative assessment of iron accumulation in the deep gray matter of multiple sclerosis by magnetic field correlation imaging. AJNR Am J Neuroradiol. 2007;28:1639–1644. [PubMed]
  • Ge Y, Law M, Johnson G, Herbert J, Babb JS, Mannon LJ, Grossman RI. Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis lesions: characterizing hemodynamic impairment and inflammatory activity. AJNR Am J Neuroradiol. 2005;26:1539–1547. [PubMed]
  • Ge Y, Zohrabian VM, Osa EO, Xu J, Jaggi H, Herbert J, Haacke EM, Grossman RI. Diminished visibility of cerebral venous vasculature in multiple sclerosis by susceptibility-weighted imaging at 3.0 Tesla. J Magn Reson Imaging. 2009;29:1190–1194. [PMC free article] [PubMed]
  • Gerber MR, Connor JR. Do oligodendrocytes mediate iron regulation in the human brain? Ann Neurol. 1989;26:95–98. [PubMed]
  • Geurts JJ, van Horssen J. The brake on neurodegeneration: Increased mitochondrial metabolism in the injured MS spinal cord. Neurology. 2010;74:710–711. [PubMed]
  • Gille G, Reichmann H. Iron-dependent functions of mitochondria--relation to neurodegeneration. J Neural Transm. 2011;118:349–359. [PubMed]
  • Gotz ME, Double K, Gerlach M, Youdim MB, Riederer P. The relevance of iron in the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci. 2004;1012:193–208. [PubMed]
  • Grant SM, Wiesinger JA, Beard JL, Cantorna MT. Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutr. 2003;133:2635–2638. [PubMed]
  • Grimaud J, Millar J, Thorpe JW, Moseley IF, McDonald WI, Miller DH. Signal intensity on MRI of basal ganglia in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1995;59:306–308. [PMC free article] [PubMed]
  • Gutsaeva DR, Suliman HB, Carraway MS, Demchenko IT, Piantadosi CA. Oxygen-induced mitochondrial biogenesis in the rat hippocampus. Neuroscience. 2006;137:493–504. [PubMed]
  • Haacke EM, Garbern J, Miao Y, Habib C, Liu M. Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol. 2010a;29:149–157. [PubMed]
  • Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z, Xuan Y, Khan O, Garbern J, Grossman RI. Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging. 2009;29:537–544. [PMC free article] [PubMed]
  • Haacke EM, Miao Y, Liu M, Habib CA, Katkuri Y, Liu T, Yang Z, Lang Z, Hu J, Wu J. Correlation of putative iron content as represented by changes in R2* and phase with age in deep gray matter of healthy adults. J Magn Reson Imaging. 2010b;32:561–576. [PMC free article] [PubMed]
  • Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958;3:41–51. [PubMed]
  • Hammann KP, Hopf HC. Monocytes constitute the only peripheral blood cell population showing an increased burst activity in multiple sclerosis patients. Int Arch Allergy Appl Immunol. 1986;81:230–234. [PubMed]
  • Han J, Seaman WE, Di X, Wang W, Willingham M, Torti FM, Torti SV. Iron Uptake Mediated by Binding of H-Ferritin to the TIM-2 Receptor in Mouse Cells. PLoS ONE. 2011;6(8):e23800. [PMC free article] [PubMed]
  • Harada T, Baba M, Torii I, Morikawa S. Ferritin selectively suppresses delayed-type hypersensitivity responses at induction or effector phase. Cell Immunol. 1987;109:75–88. [PubMed]
  • Hill JM, Ruff MR, Weber RJ, Pert CB. Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution. Proc Natl Acad Sci USA. 1985;82:4553–4557. [PubMed]
  • Hill JM, Switzer RC., 3rd The regional distribution and cellular localization of iron in the rat brain. Neuroscience. 1984;11:595–603. [PubMed]
  • Hodges YK, Reese SM, Pahl PM, Horwitz LD. Paradoxical effects of iron chelation on growth of vascular endothelial cells. J Cardiovasc Pharmacol. 2005;45:539–544. [PubMed]
  • Hogan V, White K, Edgar J, McGill A, Karim S, McLaughlin M, Griffiths I, Turnbull D, Nichols P. Increase in mitochondrial density within axons and supporting cells in response to demyelination in the Plp1 mouse model. J Neurosci Res. 2009;87:452–459. [PubMed]
  • Holley JE, Newcombe J, Whatmore JL, Gutowski NJ. Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter. Neurosci Lett. 2010;470:65–70. [PubMed]
  • Honegger CG, Krenger W, Langemann H. Measurement of free radical scavengers in the spinal cord of rats with experimental autoimmune encephalomyelitis. Neurosci Lett. 1989;98:327–332. [PubMed]
  • Huang E, Ong WY, Go ML, Connor JR. Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury. Exp. Brain Res. 2006;170:376–386. [PubMed]
  • Hulet SW, Hess EJ, Debinski W, Arosio P, Bruce K, Powers S, Connor JR. Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem. 1999a;72:868–874. [PubMed]
  • Hulet SW, Heyliger SO, Powers S, Connor JR. Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis. J Neurosci Res. 2000;61:52–60. [PubMed]
  • Hulet SW, Menzies S, Connor JR. Ferritin binding in the developing mouse brain follows a pattern similar to myelination and is unaffected by the jimpy mutation. Dev Neurosci. 2002;24:208–213. [PubMed]
  • Hulet SW, Powers S, Connor JR. Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J Neurol Sci. 1999b;165:48–55. [PubMed]
  • Huynh C, Andrews NW. Iron acquisition within host cells and the pathogenicity of Leishmania. Cell Microbiol. 2008;10:293–300. [PMC free article] [PubMed]
  • Inglese M, Park SJ, Johnson G, Babb JS, Miles L, Jaggi H, Herbert J, Grossman RI. Deep gray matter perfusion in multiple sclerosis: dynamic susceptibility contrast perfusion magnetic resonance imaging at 3 T. Arch Neurol. 2007;64:196–202. [PubMed]
  • Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J. Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res. 2010;20:345–356. [PubMed]
  • Juckett MB, Balla J, Balla G, Jessurun J, Jacob HS, Vercellotti GM. Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. Am J Pathol. 1995;147:782–789. [PubMed]
  • Kalluri R, Cantley LG, Kerjaschki D, Neilson EG. Reactive oxygen species expose cryptic epitopes associated with autoimmune goodpasture syndrome. J Biol Chem. 2000;275:20027–20032. [PubMed]
  • Kaneko Y, Kitamoto T, Tateishi J, Yamaguchi K. Ferritin immunohistochemistry as a marker for microglia. Acta Neuropathol. 1989;79:129–136. [PubMed]
  • Kaur C, Ling EA. Transient expression of transferrin receptors and localisation of iron in amoeboid microglia in postnatal rats. J Anat. 1995;186:165–173. [PubMed]
  • Kaur C, Ling EA. Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia. Neurosci Lett. 1999;262:183–1869. [PubMed]
  • Kaur C, Ling EA. Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res. 2008;5:71–81. [PubMed]
  • Kaur C, Sivakumar V, Ang LS, Sundaresan A. Hypoxic damage to the periventricular white matter in neonatal brain: role of vascular endothelial growth factor, nitric oxide and excitotoxicity. J Neurochem. 2006;98:1200–1216. [PubMed]
  • Keown P, Descamps-Latscha B. In vitro suppression of cell-mediated immunity by ferroproteins and ferric salts. Cell Immunol. 1983;80:257–266. [PubMed]
  • Khalil M, Enzinger C, Langkammer C, Tscherner M, Wallner-Blazek M, Jehna M, Ropele S, Fuchs S, Fazekas F. Quantitative assessment of brain iron by R(2)* relaxometry in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis. Mult Scler. 2009;15:1048–1054. [PubMed]
  • Knickelbein JE, de Souza AJ, Tosti R, Narayan P, Kane LP. Cutting edge: inhibition of T cell activation by TIM-2. J Immunol. 2006;177:4966–4970. [PubMed]
  • Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol. 2003;38:61–88. [PubMed]
  • Koeppen AH, Dickson AC, McEvoy JA. The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci. 1995;134(Suppl):102–112. [PubMed]
  • Kotze MJ, de Villiers JN, Rooney RN, Grobbelaar JJ, Mansvelt EP, Bouwens CS, Carr J, Stander I, du Plessis L. Analysis of the NRAMP1gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Dis. 2001;27:44–53. [PubMed]
  • Kotze MJ, de Villiers JN, Warnich L, Schmidt S, Carr J, Mansvelt E, Fourie E, van Rensburg SJ. Lack of clinical manifestation of hereditary haemochromatosisin South African patients with multiple sclerosis. Metab Brain Dis. 2006;21:109–120. [PubMed]
  • Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ. The TIM gene family: Emerging roles in immunity and disease. Nat Rev Immunol. 2003;3:454–462. [PubMed]
  • Kupershmidt L, Weinreb O, Amit T, Mandel S, Bar-Am O, Youdim MB. Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain. Neuroscience. 2011;189:345–358. [PubMed]
  • Kutzelnigg A, Lassmann H. Cortical lesions and brain atrophy in MS. J Neurol Sci. 2005;233:55–59. [PubMed]
  • Lall MM, Ferrell J, Nagar S, Fleisher LN, McGahan MC. Iron regulates L-cystine uptake and glutathione levels in lens epithelial and retinal pigment epithelial cells by its effect on cytosolic aconitase. Invest Ophthalmol. Vis Sci. 2008;49:310–419. [PubMed]
  • Langemann H, Kabiersch A, Newcombe J. Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. Eur Neurol. 1992;32:248–252. [PubMed]
  • Langkammer C, Krebs N, Goessler W, Scheurer E, Ebner F, Yen K, Fazekas F, Ropele S. Quantitative MR imaging of brain iron: a postmortem validation study. Radiology. 2010;257:455–462. [PubMed]
  • Lassmann H. Hypoxia-like tissue injuryas a component of multiple sclerosis lesions. J Neurol Sci. 2003;206:187–191. [PubMed]
  • Lassmann H. Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease. J Neural Transm. 2011;118:747–752. [PubMed]
  • Law M, Saindane AM, Ge Y, Babb JS, Johnson G, Mannon LJ, Herbert J, Grossman RI. Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology. 2004;231:645–652. [PubMed]
  • Leppert D, Ford J, Stabler G, Grygar C, Lienert C, Huber S, Miller KM, Hauser SL, Kappos L. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain. 1998;121:2327–2334. [PubMed]
  • LeVine SM. Oligodendrocytes and myelin sheaths in normal, quaking and shiverer brains are enriched in iron. J Neurosci Res. 1991;29:413–419. [PubMed]
  • LeVine SM. Iron deposits in multiple sclerosis and Alzheimer’s disease brains. Brain Res. 1997;760:298–303. [PubMed]
  • LeVine SM, Brown DC. IL-6 and TNFalpha expression in brains of twitcher, quaking and normal mice. J Neuroimmunol. 1997;73:47–56. [PubMed]
  • LeVine SM, Chakrabarty A. The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci. 2004;1012:252–266. [PubMed]
  • LeVine SM, Maiti S, Emerson MR, Pedchenko TV. Apoferritin attenuates experimental allergic encephalomyelitis in SJL mice. Dev Neurosci. 2002;24:177–183. [PubMed]
  • LeVine SM, Lynch SG, Ou CN, Wulser MJ, Tam E, Boo N. Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients. Brain Res. 1999;821:511–515. [PubMed]
  • LeVine SM, Macklin WB. Iron-enriched oligodendrocytes: a reexamination of their spatial distribution. J Neurosci Res. 1990;26:508–512. [PubMed]
  • LeVine SM, Torres MV. Morphological features of degenerating oligodendrocytes in twitcher mice. Brain Res. 1992;587:348–352. [PubMed]
  • LeVine SM, Wetzel DL. Chemical analysis of multiple sclerosis lesions by FT-IR microspectroscopy. Free Radic Biol Med. 1998;25:33–41. [PubMed]
  • Li H, Swiercz R, Englander EW. Elevated metals compromise repair of oxidative DNA damage via the base excision repair pathway: implications of pathologic iron overload in the brain on integrity of neuronal DNA. J Neurochem. 2009;110:1774–1783. [PMC free article] [PubMed]
  • Li L, Fang CJ, Ryan JC, Niemi EC, Lebrón JA, Björkman PJ, Arase H, Torti FM, Torti SV, Nakamura MC, Seaman WE. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci USA. 2010;107:3505–3510. [PubMed]
  • Lin HH, Connor JR. The development of the transferrin-transferrin receptor system in relation to astrocytes, MBP and galactocerebroside in normal and myelin-deficient rat optic nerves. Brain Res Dev Brain Res. 1989;49:281–293. [PubMed]
  • Liuzzi GM, Trojano M, Fanelli M, Avolio C, Fasano A, Livrea P, Riccio P. Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis. Mult Scler. 2002;8:222–228. [PubMed]
  • Lok CN, Ponka P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem. 1999;274:24147–24152. [PubMed]
  • Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain. 1999;122:2279–2295. [PubMed]
  • Lynch SG, Fonseca T, LeVine SM. A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol (Noisy-le-grand) 2000;46:865–869. [PubMed]
  • Lynch SG, Peters K, LeVine SM. Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult Scler. 1996;2:157–160. [PubMed]
  • Mackenzie B, Hediger MA. SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch. 2004;447:571–579. [PubMed]
  • MacMicking JD, Willenborg DO, Weidemann MJ, Rockett KA, Cowden WB. Elevated secretion of reactive nitrogen and oxygen intermediates by inflammatory leukocytes in hyperacute experimental autoimmune encephalomyelitis: enhancement by the soluble products of encephalitogenic T cells. J Exp Med. 1992;176:303–307. [PMC free article] [PubMed]
  • Maeda A, Sobel RA. Matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions. J Neuropathol Exp Neurol. 1996;55:300–309. [PubMed]
  • Mahad D, Lassmann H, Turnbull D. Review: Mitochondria and disease progression in multiple sclerosis. Neuropathol Appl Neurobiol. 2008a;34:577–589. [PMC free article] [PubMed]
  • Mahad D, Ziabreva I, Lassmann H, Turnbull D. Mitochondrial defects in acute multiple sclerosis lesions. Brain. 2008b;131:1722–1735. [PubMed]
  • Mairuae N, Connor JR, Cheepsunthorn P. Increased cellular iron levels affect matrix metalloproteinase expression and phagocytosis in activated microglia. Neurosci Lett. 2011;500:36–40. [PubMed]
  • Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta. 2010;1802:66–79. [PMC free article] [PubMed]
  • Marder E, Gupta P, Greenberg BM, Frohman EM, Awad AM, Bagert B, Stüve O. No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis. Arch Neurol. 2011 in press. [PubMed]
  • Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, Na HM, Gutekunst CA, Gearing M, Trojanowski JQ, Anderson M, Chu CT, Peng J, Greenamyre JT. A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson’s disease. Neurobiol Dis. 2009;34:417–431. [PMC free article] [PubMed]
  • Matute C. Glutamate and ATP signalling in white matter pathology. J Anat. 2011;219:53–64. [PubMed]
  • Matute C, Sánchez-Gómez MV, Martínez-Millán L, Miledi R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci USA. 1997;94:8830–8835. [PubMed]
  • Matzner Y, Hershko C, Polliack A, Konijn AM, Izak G. Suppressive effect of ferritin on in vitro lymphocyte function. Br J Haematol. 1979;42:345–353. [PubMed]
  • McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol. 2007;8:913–919. [PubMed]
  • McGahan MC, Harned J, Mukunnemkeril M, Goralska M, Fleisher L, Ferrell JB. Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am J Physiol Cell Physiol. 2005;288:C1117–1124. [PubMed]
  • Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper HM. Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J Neurochem. 2001;77:1386–1395. [PubMed]
  • Mitchell KM, Dotson AL, Cool KM, Chakrabarty A, Benedict SH, LeVine SM. Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis. Mult Scler. 2007;13:1118–1126. [PubMed]
  • Miyachi S, Lu X, Imanishi M, Sawada K, Nambu A, Takada M. Somatotopically arranged inputs from putamen and subthalamic nucleus to primary motor cortex. Neurosci Res. 2006;56:300–308. [PubMed]
  • Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol. 2000;20:77–95. [PubMed]
  • Moos T, Morgan EH. The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann N Y Acad Sci. 2004;1012:14–26. [PubMed]
  • Moos T, Rosengren Nielsen T, Skjorringe T, Morgan EH. Iron trafficking inside the brain. J Neurochem. 2007;103:1730–1740. [PubMed]
  • Moos T, Trinder D, Morgan EH. Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and beta2-microglobulin deficient mouse brain. Cell Mol Biol (Noisy-le-grand) 2000;46:549–561. [PubMed]
  • Neema M, Arora A, Healy BC, Guss ZD, Brass SD, Duan Y, Buckle GJ, Glanz BI, Stazzone L, Khoury SJ, Weiner HL, Guttmann CR, Bakshi R. Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis. J Neuroimaging. 2009;19:3–8. [PMC free article] [PubMed]
  • Norstrand IF, Craelius W. A trial of deferoxamine(Desferal) in the treatment of multiple sclerosis. A pilot study. Clinical Trials. 1989;26:365–369.
  • Omori N, Maruyama K, Jin G, Li F, Wang SJ, Hamakawa Y, Sato K, Nagano I, Shoji M, Abe K. Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurol Res. 2003;25:275–279. [PubMed]
  • Ong WY, Ren MQ, Makjanic J, Lim TM, Watt F. A nuclear microscopic study of elemental changes in the rat hippocampus after kainate-induced neuronal injury. J Neurochem. 1999;72:1574–1579. [PubMed]
  • Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta. 2010;1802:228–234. [PubMed]
  • Onyszchuk G, LeVine SM, Brooks WM, Berman NE. Post-acute pathological changes in the thalamus and internal capsule in aged mice following controlled cortical impact injury: a magnetic resonance imaging, iron histochemical, and glial immunohistochemical study. Neurosci Lett. 2009;452:204–208. [PMC free article] [PubMed]
  • Oweida AJ, Dunn EA, Karlik SJ, Dekaban GA, Foster PJ. Iron-oxide labeling of hematogenous macrophages in a model of experimental autoimmune encephalomyelitis and the contribution to signal loss in fast imaging employing steady state acquisition (FIESTA) images. J Magn Reson Imaging. 2007;26:144–151. [PubMed]
  • Pampliega O, Domercq M, Soria FN, Villoslada P, Rodríguez-Antigüedad A, Matute C. Increased expression of cystine/glutamate antiporter in multiple sclerosis. J Neuroinflammation. 2011;8:63. [PMC free article] [PubMed]
  • Paradkar PN, Roth JA. Nitric oxide transcriptionally down-regulates specific isoforms of divalent metal transporter (DMT1) via NF-kappaB. J Neurochem. 2006;96:1768–1777. [PubMed]
  • Pedchenko TV, LeVine SM. Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice. J Neuroimmunol. 1998;84:188–197. [PubMed]
  • Pelizzoni I, Macco R, Morini MF, Zacchetti D, Grohovaz F, Codazzi F. Iron handling in hippocampal neurons: activity-dependent iron entry and mitochondria-mediated neurotoxicity. Aging Cell. 2011;10:172–183. [PubMed]
  • Penkowa M, Espejo C, Martinez-Caceres EM, Poulsen CB, Montalban X, Hidalgo J. Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis. J Neuroimmunol. 2001;119:248–260. [PubMed]
  • Peterson JW, Bö L, Mörk S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389–400. [PubMed]
  • Petzold A, Eikelenboom MJ, Gveric D, Keir G, Chapman M, Lazeron RH, Cuzner ML, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G. Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain. 2002;125:1462–1473. [PubMed]
  • Piñero DJ, Connor JR. Iron in the Brain: An Important Contributor in Normal and Diseased States. Neuroscientist. 2000;6:435–453.
  • Pirko I, Johnson AJ, Chen Y, Lindquist DM, Lohrey AK, Ying J, Dunn RS. Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. Neuroimage. 2011;54:802–806. [PMC free article] [PubMed]
  • Pirko I, Johnson AJ, Lohrey AK, Chen Y, Ying J. Deep gray matter T2 hypointensity correlates with disability in a murine model of MS. J Neurol Sci. 2009;282:34–38. [PMC free article] [PubMed]
  • Prinster A, Quarantelli M, Orefice G, Lanzillo R, Brunetti A, Mollica C, Salvatore E, Morra VB, Coppola G, Vacca G, Alfano B, Salvatore M. Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study. Neuroimage. 2006;29:859–867. [PubMed]
  • Proescholdt MA, Jacobson S, Tresser N, Oldfield EH, Merrill MJ. Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J Neuropathol Exp Neurol. 2002;61:914–925. [PubMed]
  • Putnam T. Evidences of vascular occlusion in multiple sclerosis and “encephalomyelitis” Arch Neurol Psychiatry. 1937;37:1298–1321.
  • Qian ZM, Wu XM, Fan M, Yang L, Du F, Yung WH, Ke Y. Divalent metal transporter 1 is a hypoxia-inducible gene. J Cell Physiol. 2011;226:1596–1603. [PubMed]
  • Rajan KS, Colburn RW, Davis JM. Distribution of metal ions in the subcellular fractions of several rat brain areas. Life Sci. 1976;18:423–431. [PubMed]
  • Ram M, Sherer Y, Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol. 2006;26:299–307. [PubMed]
  • Ramagopalan SV, Cukjati M, Cernilec M, DeLuca GC, Dyment DA, Degenhardt A, Sadovnick AD, Serbec VC, Ebers GC, Duquette P. Mutations in the hemochromatosis gene and the clinical outcome of multiple sclerosis. J Neuroimmunol. 2008;203:104–107. [PubMed]
  • Rausch M, Hiestand P, Foster CA, Baumann DR, Cannet C, Rudin M. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2004;20:16–24. [PubMed]
  • Recalcati S, Invernizzi P, Arosio P, Cairo G. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun. 2008;30:84–89. [PubMed]
  • Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Rahmanto YS, Sheftel AD, Ponka P. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci USA. 2010;107:10775–10782. [PubMed]
  • Ristić S, Lovrecić L, Brajenović-Milić B, Starcević-Cizmarević N, Jazbec SS, Sepcić J, Kapović M, Peterlin B. Mutations in the hemochromatosis gene (HFE) and multiple sclerosis. Neurosci Lett. 2005;383:301–304. [PubMed]
  • Robb SJ, Connor JR. An in vitro model for analysis of oxidative death in primary mouse astrocytes. Brain Res. 1998;788:125–132. [PubMed]
  • Robb SJ, Robb-Gaspers LD, Scaduto RC, Jr, Thomas AP, Connor JR. Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes. J Neurosci Res. 1999;55:674–686. [PubMed]
  • Roediger B, Armati PJ. Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis. 2003;13:222–229. [PubMed]
  • Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem. 1990;265:14572–14578. [PubMed]
  • Roscoe WA, Welsh ME, Carter DE, Karlik SJ. VEGF and angiogenesis in acute and chronic MOG((35-55)) peptide induced EAE. J Neuroimmunol. 2009;209:6–15. [PubMed]
  • Ruiz de Almodovar C, Lambrechts D, Mazzone M, Carmeliet P. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009;89:607–48. [PubMed]
  • Russo C, Smoker WR, Kubal W. Cortical and subcortical T2 shortening in multiple sclerosis. AJNR Am J Neuroradiol. 1997;18:124–126. [PubMed]
  • Ruuls SR, Bauer J, Sontrop K, Huitinga I, t Hart BA, Dijkstra CD. Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats. J Neuroimmunol. 1995;56:207–217. [PubMed]
  • Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nunez MT, Garrick MD, Raisman-Vozari R, Hirsch EC. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci USA. 2008;105:18578–18583. [PubMed]
  • Saleh MC, Espinosa delos Monteros A, de Arriba Zerpa GA, Fontaine I, Piaud O, Djordjijevic D, Baroukh N, Garcia Otin AL, Ortiz E, Lewis S, Fiette L, Santambrogio P, Belzung C, Connor JR, de Vellis J, Pasquini JM, Zakin MM, Baron B, Guillou F. Myelination and motor coordination are increased in transferrin transgenic mice. J Neurosci Res. 2003;72:587–594. [PubMed]
  • Saleppico S, Mazzolla R, Boelaert JR, Puliti M, Barluzzi R, Bistoni F, Blasi E. Iron regulates microglial cell-mediated secretory and effector functions. Cell Immunol. 1996;170:251–259. [PubMed]
  • Sastry S, Arendash GW. Time-dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. Neuroscience. 1995;67:649–666. [PubMed]
  • Sayre LM, Moreira PI, Smith MA, Perry G. Metal ions and oxidative protein modification in neurological disease. Ann Ist Super Sanita. 2005;41:143–164. [PubMed]
  • Seabrook TJ, Littlewood-Evans A, Brinkmann V, Pöllinger B, Schnell C, Hiestand PC. Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions. J Neuroinflammation. 2010;7:95. [PMC free article] [PubMed]
  • Sfagos C, Makis AC, Chaidos A, Hatzimichael EC, Dalamaga A, Kosma K, Bourantas KL. Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients. Mult Scler. 2005;11:272–275. [PubMed]
  • Sharp CD, Hines I, Houghton J, Warren A, Jackson TH, 4th, Jawahar A, Nanda A, Elrod JW, Long A, Chi A, Minagar A, Alexander JS. Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart Circ Physiol. 2003;285:H2592–H2598. [PubMed]
  • Sharp CD, Houghton J, Elrod JW, Warren A, Jackson TH, 4th, Jawahar A, Nanda A, Minagar A, Alexander JS. N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress. Am J Physiol Heart Circ Physiol. 2005;288:H1893–H1899. [PubMed]
  • Shoham S, Wertman E, Ebstein RP. Iron accumulation in the rat basal ganglia after excitatory amino acid injections--dissociation from neuronal loss. Exp Neurol. 1992;118:227–241. [PubMed]
  • Silkis I. The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. II. Mechanism of synergistic modulation of thalamic activity via the direct and indirect pathways through the basal ganglia. Biosystems. 2001;59:7–14. [PubMed]
  • Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, Hainzl A, Schatz S, Qi Y, Schlecht A, Weiss JM, Wlaschek M, Sunderkotter C, Scharffetter-Kochanek K. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest. 2011;121:985–997. [PMC free article] [PubMed]
  • Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab. 2009;29:1867–1878. [PubMed]
  • Sinor AD, Irvin SM, Cobbs CS, Chen J, Graham SH, Greenberg DA. Hypoxic induction of vascularendothelial growth factor (VEGF) protein in astroglial cultures. Brain Res. 1998;812:289–291. [PubMed]
  • Smirnov IM, Bailey K, Flowers CH, Garrigues NW, Wesselius LJ. Effects of TNF-alpha and IL-1beta on iron metabolism by A549 cells and influence on cytotoxicity. Am J Physiol. 1999;277:L257–263. [PubMed]
  • Srinivasan R, Ratiney H, Hammond-Rosenbluth KE, Pelletier D, Nelson SJ. MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis. Magn Reson Imaging. 2010;28:163–170. [PubMed]
  • Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain. 2005;128:1016–1025. [PubMed]
  • Stoll G, Wesemeier C, Gold R, Solymosi L, Toyka KV, Bendszus M. In vivo monitoring of macrophage infiltration in experimental autoimmune neuritis by magnetic resonance imaging. J Neuroimmunol. 2004;149:142–146. [PubMed]
  • Sun D, Tani M, Newman TA, Krivacic K, Phillips M, Chernosky A, Gill P, Wei T, Griswold KJ, Ransohoff RM, Weller RO. Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage. J Neuropathol Exp Neurol J Neuropathol Exp Neurol. 2000;59:1031–1043. [PubMed]
  • Sundstrom P, Wahlin A, Ambarki K, Birgander R, Eklund A, Malm J. Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann Neurol. 2010;68:255–259. [PubMed]
  • Sweeney ME, Slusser JG, Lynch SG, Benedict SH, Garcia SL, Rues L, LeVine SM. Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing-remitting multiple sclerosis subjects. Int Immunopharmacol. 2011 In press. [PMC free article] [PubMed]
  • Tacchini L, Gammella E, De Ponti C, Recalcati S, Cairo G. Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. J Biol Chem. 2008;283:20674–20686. [PMC free article] [PubMed]
  • Takeuchi H, Mizuno T, Zhang G, Wang J, Kawanokuchi J, Kuno R, Suzumura A. Neuritic beading induced by activated microgliais an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem. 2005;280:10444–10454. [PubMed]
  • Tanaka R, Iwasaki Y, Koprowski H. Ultrastructural studies of perivascular cuffing cells in multiple sclerosis brain. Am J Pathol. 1975;81:467–478. [PubMed]
  • Taylor MC, Kelly JM. Iron metabolism in trypanosomatids, and its crucial role in infection. Parasitology. 2010;137:899–917. [PubMed]
  • Tjoa CW, Benedict RH, Weinstock-Guttman B, Fabiano AJ, Bakshi R. MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis. J Neurol Sci. 2005;234:17–24. [PubMed]
  • Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR. Oligodendrocytes and myelination: the role of iron. Glia. 2009;57:467–478. [PubMed]
  • Todorich B, Zhang X, Connor JR. H-ferritinis the major source of iron for oligodendrocytes. Glia. 2011;59:927–935. [PubMed]
  • Todorich B, Zhang X, Slagle-Webb B, Seaman WE, Connor JR. Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem. 2008;107:1495–1505. [PubMed]
  • Tovar-Y-Romo LB, Tapia R. VEGF protects spinal motor neurons against chronic excitotoxic degeneration in vivo by activation of PI3-K pathway and inhibition of p38MAPK. J Neurochem. 2010;115:1090–1101. [PubMed]
  • Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278–285. [PubMed]
  • Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol. 1999;12:295–302. [PubMed]
  • Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 2009;8:280–291. [PubMed]
  • Trebst C, Staugaitis SM, Tucky B, Wei T, Suzuki K, Aldape KD, Pardo CA, Troncoso J, Lassmann H, Ransohoff RM. Chemokine receptors on infiltrating leucocytes in inflammatory pathologies of the central nervous system (CNS) Neuropathol Appl Neurobiol. 2003;29:584–595. [PubMed]
  • Trigwell SM, Radford PM, Page SR, Loweth AC, James RF, Morgan NG, Todd I. Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. Clin Exp Immunol. 2001;126:242–249. [PubMed]
  • Tsuji Y, Miller LL, Miller SC, Torti SV, Torti FM. Tumor necrosis factor-alpha and interleukin 1-alpha regulate transferrin receptor in human diploid fibroblasts. Relationship to the induction of ferritin heavy chain. J Biol Chem. 1991;266:7257–7261. [PubMed]
  • van Toorn R, Schoeman JF, Solomons R, Rensburg MA, van Rensburg SJ. Iron status in children with recurrent episodes of tumefactive cerebral demyelination. J Child Neurol. 2010;25:1401–1407. [PubMed]
  • Vercellino M, Masera S, Lorenzatti M, Condello C, Merola A, Mattioda A, Tribolo A, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P. Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J Neuropathol Exp Neurol. 2009;68:489–502. [PubMed]
  • Vercellino M, Merola A, Piacentino C, Votta B, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol. 2007;66:732–739. [PubMed]
  • Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P. Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol. 2005;64:1101–1107. [PubMed]
  • Wakefield AJ, More LJ, Difford J, McLaughlin JE. Immunohistochemical study of vascular injury in acute multiple sclerosis. J Clin Pathol. 1994;47:129–133. [PMC free article] [PubMed]
  • Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011;434:365–381. [PMC free article] [PubMed]
  • Wang XS, Ong WY, Connor JR. Increase in ferric and ferrous iron in the rat hippocampus with time after kainate-induced excitotoxic injury. Exp Brain Res. 2002;143:137–148. [PubMed]
  • Warnke C, Meyer Zu, Hörste G, Hartung HP, Stüve O, Kieseier BC. Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr Dis Treat. 2009;5:333–340. [PMC free article] [PubMed]
  • Werner P, Pitt D, Raine CS. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol. 2001;50:169–180. [PubMed]
  • Williams R, Rohr AM, Wang W-T, Choi I-Y, Lee P, Berman NEJ, Lynch SG, LeVine SM. Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis. BMC Neuroscience. 2011;12:59. [PMC free article] [PubMed]
  • Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, Wintjes LT, Smeitink JA, Geurts JJ, De Vries HE, van der Valk P, van Horssen J. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol. 2009;219:193–204. [PubMed]
  • Wong R. NMDA receptors expressed in oligodendrocytes. Bioessays. 2006;28:460–464. [PubMed]
  • Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A. Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurol. 2010;75:1617–1622. [PubMed]
  • Xu X, Wang Q, Zhang M. Age, gender, and hemispheric differences in iron deposition in the human brain: an in vivo MRI study. Neuroimage. 2008;40:35–42. [PubMed]
  • Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J. Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke. 2008;39:3057–3063. [PMC free article] [PubMed]
  • Yu J, Guo Y, Sun M, Li B, Zhang Y, Li C. Iron is a potential key mediator of glutamate excitotoxicity inspinal cord motor neurons. Brain Res. 2009;1257:102–107. [PubMed]
  • Zamboni P. The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med. 2006;99:589–593. [PMC free article] [PubMed]
  • Zamboni P, Lanzara S, Mascoli F, Caggiati A, Liboni A. Inflammation in venous disease. Int Angiol. 2008;27:361–369. [PubMed]
  • Zamboni P, Menegatti E, Bartolomei I, Galeotti R, Malagoni AM, Tacconi G, Salvi F. Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res. 2007;4:252–258. [PubMed]
  • Zamboni P, Scapoli G, Lanzara V, Izzo M, Fortini P, Legnaro R, Palazzo A, Tognazzo S, Gemmati D. Serum iron and matrix metalloproteinase-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg. 2005;31:644–649. [PubMed]
  • Zhang S, Wang J, Song N, Xie J, Jiang H. Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol Aging. 2009;30:1466–1476. [PubMed]
  • Zhang X, Haaf M, Todorich B, Grosstephan E, Schieremberg H, Surguladze N, Connor JR. Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia. 2005;52:199–208. [PubMed]
  • Zhang X, Surguladze N, Slagle-Webb B, Cozzi A, Connor JR. Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia. 2006;54:795–804. [PubMed]
  • Zhang Y, Zabad RK, Wei X, Metz LM, Hill MD, Mitchell JR. Deepgrey matter “black T2” on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis. Mult Scler. 2007;13:880–883. [PubMed]
  • Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106:829–838. [PMC free article] [PubMed]