Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells
TL;DR: The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin.
Abstract: Inflammation and iron accumulation are present in a variety of neurodegenerative diseases that include Alzheimer's disease and Parkinson's disease. The study of the putative association between inflammation and iron accumulation in central nervous system cells is relevant to understand the contribution of these processes to the progression of neuronal death. In this study, we analyzed the effects of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) and of lipopolysaccharide on total cell iron content and on the expression and abundance of the iron transporters divalent metal transporter 1 (DMT1) and Ferroportin 1 (FPN1) in neurons, astrocytes and microglia obtained from rat brain. Considering previous reports indicating that inflammatory stimuli induce the systemic synthesis of the master iron regulator hepcidin, we identified brain cells that produce hepcidin in response to inflammatory stimuli, as well as hepcidin-target cells. We found that inflammatory stimuli increased the expression of DMT1 in neurons, astrocytes, and microglia. Inflammatory stimuli also induced the expression of hepcidin in astrocytes and microglia, but not in neurons. Incubation with hepcidin decreased the expression of FPN1 in the three cell types. The net result of these changes was increased iron accumulation in neurons and microglia but not in astrocytes. The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin. This connection may potentially contribute to the progression of neurodegenerative diseases by enhancing iron-induced oxidative damage.
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TL;DR: MRI can often identify changes in iron homoeostasis, thus providing a potential diagnostic biomarker of neurodegenerative diseases and an important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood-brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.
Abstract: Summary In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood–brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.
1,089 citations
TL;DR: Considering the above issues, age‐related accumulation of neuromelanin in dopamine neurons shows an interesting link between aging and neurodegeneration.
454 citations
Cites background from "Inflammation alters the expression ..."
..., 2007; Conde and Streit, 2006; Gao and Hong, 2008), since neuroinflammation can perturb iron homeostasis on different brain cells as demonstrated in in vitro studies that used both mouse and rat cell cultures (Rathore et al., 2012; Urrutia et al., 2013); (iii) increased...
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...As a consequence, these scavenger cells become iron rich and additionally in activated microglia iron homeostasis is perturbed as well as ferritin expression, as demonstrated in cell cultures (Cheepsunthorn et al., 2001; Rathore et al., 2012; Urrutia et al., 2013)....
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...…iron homeostasis on different brain cells as demonstrated in in vitro studies that used both mouse and rat cell cultures (Rathore et al., 2012; Urrutia et al., 2013); (iii) increased expression of lactoferrin receptors (involved in iron uptake through lactoferrin) in neurons and microvessels…...
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TL;DR: The characteristics of p38 signaling in Macrophage-mediated inflammation are summarized and the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases is discussed.
Abstract: Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.
275 citations
TL;DR: Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis, making it a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases.
Abstract: Iron fulfils a central role in many essential biochemical processes in human physiology; thus, proper processing of iron is crucial. Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis. Consequently, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents are likely to have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are currently available.
244 citations
TL;DR: How metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau) are reviewed to increase the awareness of metals as players in the onset and progression of AD.
240 citations
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TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
4,319 citations
TL;DR: It is reported that hepcidin bound to ferroportin in tissue culture cells, leading to decreased export of cellular iron and the posttranslational regulation of ferroports by hePCidin may complete a homeostatic loop.
Abstract: Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.
4,109 citations
"Inflammation alters the expression ..." refers background in this paper
...The physiological function of hepcidin is to decrease circulating iron levels through down-regulation of FPN1 in macrophages (Nemeth et al. 2004)....
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TL;DR: This protocol provides protocols for preparing low-density dissociated-cell cultures of hippocampal neurons from embryonic rats or mice that become appropriately polarized, develop extensive axonal and dendritic arbors and form numerous, functional synaptic connections with one another.
Abstract: We provide protocols for preparing low-density dissociated-cell cultures of hippocampal neurons from embryonic rats or mice. The neurons are cultured on polylysine-treated coverslips, which are suspended above an astrocyte feeder layer and maintained in serum-free medium. When cultured according to this protocol, hippocampal neurons become appropriately polarized, develop extensive axonal and dendritic arbors and form numerous, functional synaptic connections with one another. Hippocampal cultures have been used widely for visualizing the subcellular localization of endogenous or expressed proteins, for imaging protein trafficking and for defining the molecular mechanisms underlying the development of neuronal polarity, dendritic growth and synapse formation. Preparation of glial feeder cultures must begin 2 weeks in advance, and it takes 5 d to prepare coverslips as a substrate for neuronal growth. Dissecting the hippocampus and plating hippocampal neurons takes 2-3 h.
1,452 citations
"Inflammation alters the expression ..." refers methods in this paper
...Primary cultures of embryonic rat hippocampal neurons were obtained as described (Kaech and Banker 2006)....
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TL;DR: Hepcidin, ferroportin and their regulators represent potential targets for the diagnosis and treatment of iron disorders and anemias.
995 citations
"Inflammation alters the expression ..." refers background in this paper
...As described for macrophages and other cell types (Ganz and Nemeth 2012), hepcidin induced a canonical down-regulation of FPN1 protein in neurons....
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TL;DR: The results suggest that an immune response may occur in the nigrostriatal dopaminergic regions in Parkinson's disease and that TNF-alpha may be related, at least in part, to the neuronal degeneration.
876 citations
"Inflammation alters the expression ..." refers background in this paper
...Indeed, the brains of PD patients contain elevated levels of cytokines, including IL1-b, IL2, IL4, IL-6, and TNF-a (Mogi et al. 1994a, b, 1996), while in AD microglia surrounding Ab plaques show increased secretion of Received January 4, 2013; revised manuscript received February 27, 2013; accepted…...
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...Indeed, the brains of PD patients contain elevated levels of cytokines, including IL1-b, IL2, IL4, IL-6, and TNF-a (Mogi et al. 1994a, b, 1996), while in AD microglia surrounding Ab plaques show increased secretion of Received January 4, 2013; revised manuscript received February 27, 2013; accepted March 1, 2013....
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