Hepcidin, an emerging and important player in brain iron homeostasis

Driton Vela, Driton Vela

Abstract

Hepcidin is emerging as a new important factor in brain iron homeostasis. Studies suggest that there are two sources of hepcidin in the brain; one is local and the other comes from the circulation. Little is known about the molecular mediators of local hepcidin expression, but inflammation and iron-load have been shown to induce hepcidin expression in the brain. The most important source of hepcidin in the brain are glial cells. Role of hepcidin in brain functions has been observed during neuronal iron-load and brain hemorrhage, where secretion of abundant hepcidin is related with the severity of brain damage. This damage can be reversed by blocking systemic and local hepcidin secretion. Studies have yet to unveil its role in other brain conditions, but the rationale exists, since these conditions are characterized by overexpression of the factors that stimulate brain hepcidin expression, such as inflammation, hypoxia and iron-overload.

Keywords: Alzheimer’s disease; Astrocytes; Brain hemorrhage; Hepcidin; Inflammation.

Figures

Fig. 1
Fig. 1
Systemic iron homeostasis. Trivalent iron is reduced by ferrireductases (DcytB) before its absorption through DMT1 in enterocytes. Once inside enterocytes iron binds with chaperones like PCBs. PCBs act like intracellular iron transporters that distribute this metal to ferritin depots and probably to FPN. FPN is the main exporter of iron out of cells. This action of FPN is helped by ferrioxidases (like Heph). After its export out of cells, iron is immediately bound to Tf. This complex circulates in plasma and finally binds with its target, which is TFR1. Systemic iron availability is controlled by hepcidin. Hepcidin is produced in hepatocytes in response to different stimuli. Iron-mediated pathways are the main factors that induce hepcidin expression. The most important pathways activate LSECs, which in turn produce BMP6. BMP6 acts in a paracrine manner through BMPR in hepatocytes. BMPR activates SMAD pathway, which induces hepcidin expression. Iron pathways induce hepcidin expression through membrane proteins, like TFR2 and HFE, as well. Inflammatory signals are also important upregulators of hepcidin by acting through JAK/STAT pathway. Negative control is realized through ERFE, which is produced from erythrocyte precursors. BMP6 bone morphogenetic protein 6, BMPR BMP receptor, DcytB duodenal cytochrome B, DMT1 divalent metal transporter 1, ERFE erythroferrone, FPN ferroportin, HAMP hepcidin antimicrobial peptide, Heph hephaestin, HFE hemochromatosis protein, JAK2/STAT3 janus kinase 2/signal transducer and activator of transcription 3, LSEC liver sinusoidal endothelial cells, PCB poly-(rC)-binding protein, SMAD S-mothers against decapentaplegic, TFR transferrin receptor
Fig. 2
Fig. 2
Hepcidin regulation and action in brain cells. Hepcidin expression in the brain is often induced by inflammatory stimuli. Inflammatory cytokines increase iron import through DMT1, and decrease iron export due to FPN downregulation. This increases cellular iron-load, especially in neurons. During iron-load conditions, astrocytes and microglia have been shown to increase hepcidin production. This might be the case for neurons as well, but the data are still inconclusive. Use of ad-hepcidin protects neurons during iron-overload conditions, by controlling the activity of iron import and export proteins, like TFR1, DMT1, FPN. Also, ad-hepcidin reduces iron flux from BMVEC, which reduces brain iron-load. Recent data suggest an important role for Zip8 and Steap2 for NTBI entry into brain cells. BMVEC brain microvascular endothelial cell, CIL cellular iron-load, DMT1 divalent metal transporter 1, FPN ferroportin, Hepc hepcidin, IL-6 interleukin 6, NTBI non-transferrin bound iron, TFR1 transferrin receptor 1

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