Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells

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-a) 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.

Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

“…Our results show mRNA induction at 4 and 24 h in both the ispsilateral and contralateral sides of the brain, which implicates a specific pathway for iron homeostasis in the brain. This is consistent with recent studies showing induction of hepcidin mRNA in the brain in a D-galactose model of aging (Wei et al, 2014) in cultured astrocytes and microglia, but not in neurons (Urrutia et al, 2013), as well as a consequence of ischemia in an MCA occlusion model (Ding et al, 2011).…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…Once in the cytosol, Fe(II) can be utilised for various essential metabolic processes such as the synthesis of iron-sulphur proteins, or sequestrated by cytosolic ferritin and mitochondrial ferritin (FtMt), which offers protection against the advent of the Fenton reaction. Iron is removed from neurones by ferroportin, supported by the multi-coppercontaining ferroxidase caeruloplasmin and sAPP, which both act to stabilise ferroportin at the cell surface levels of neuronal iron accumulation over time in an environment of neuroinflammation [330,331,333].…”

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“…38 Inflammation can also upregulate hepcidin synthesis by various brain cells (astrocytes, microglia, and neurons), which results in accumulation of intracellular iron and lack of iron availability for important developmental processes. 57 These changes in iron metabolism may be detrimental to cognitive development, as oligodendrocytes require iron for myelin synthesis, a process accomplished by the release of iron from neuronal iron stores during myelination. Iron is also required for monoamine synthesis, neuronal metabolic activity, and the proper development of neuronal morphology.…”