Iron, Neuroinflammation and Neurodegeneration

Abstract

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.

Keywords: astrocytes; iron; iron homeostasis; microglia; neuroinflammation.

Figure 1

Mechanisms of iron import, handling and export. Dietary ferric iron is reduced to ferrous iron by DCYTB and imported via DMT1. Once in the cytosol, iron is chaperoned by PCBP1 and delivered to Ferritin for storage. In iron depletion conditions, NCOA4 mediates lysosomal ferritinophagy and cellular iron release via FPN. Iron is oxidised to ferric iron via Ceruloplasmin or Hephaestin and loaded onto transferrin to be delivered via the bloodstream to all cell types. In the circulation, diferric Tf (Fe₂Tf binds to the transferrin receptor (TfR1), and once bound to TfR1, the TfR1/Fe₂-Tf complex is internalised into an endosome which is acidified by a proton pump to a pH of 5.6. Under these conditions Fe³⁺ is released from the complex and is reduced to Fe²⁺ by the reductase Steap3. The Fe²⁺ is then transported into the cytoplasm by Divalent Metal Transporter 1 (DMT1), and the ApoTf/TfR1 complex is returned to the cell surface where it is released back into the circulation for reutilisation. As we will see later, there is a second transferrin receptor, TfR2, which is involved in systemic iron homeostasis. Cellular iron homeostasis is orchestrated via the IRE/IRP system that regulates the expression of TFR1 and DMT1, and of both chains of ferritin and the iron exporter Fpn1. Non transferrin bound iron (NTBI) is imported via the Zinc–Iron-Proteins ZIP8 and ZIP14. In haemolytic conditions, haemoglobin and haem released into the circulation are respectively bound to haptoglobin (HP) and haemopexin (HPX) to be internalised by the cell. HO-1 cleaves haem to form biliverdin and releases ferrous iron. Newly synthetised haem is exported via FLVCR [6].

Figure 2

The 25-residue peptide hormone, hepcidin, produced by the liver, is the central regulator of systemic iron metabolism. When hepcidin is released into the circulation, it binds to the iron exporter, ferroportin, resulting in internalisation and degradation of ferroportin, thereby preventing the release of iron from duodenal enterocytes and macrophages of the reticuloendothelial system. Hepcidin expression is controlled by several factors: (i) the amount of available iron, represented by body iron stores (centre) and transferrin saturation [TSAT] (right); (ii) inflammation, essentially via the proinflammatory cytokine, Interleukin 6 [IL6] left); and (iii) the iron requirement for erythropoiesis (centre). Replete iron stores increase the amount of the cytokines BMP2 and 6 (bone morphogenic protein 2 and 6) which, together with the cofactor hemojuvelin (HJV), activates the BMP/SMAD signaling pathway, resulting in hepcidin induction. In inflammation-related functional iron deficiency, hepcidin expression is increased via the JAK/STAT signaling pathway. As a function of the functional iron deficiency, the kidney produces erythropoietin [EPO], which increases erythropoiesis. The erythroid precursor cells continue to produce erythroferron [ERFE], which inhibits the BMP/SMAP pathway, decreasing hepcidin expression. Abbreviations not defined above HFE, high iron; JAK Janus kinase; STAT, signal transducers and activators of transcription; SMAD, small-body-size mothers against decapentaplegic homolog 1; TFR2 transferrin receptor 2 [13].

Figure 3

Stages of microglia activation from a ramified structure to an amoeboid form. A section of a Parkinson’s brain, of the region, substantia nigra showing 3 different stages of microglia activation. IbA staining.

Figure 4

Activated microglia showing receptors involved in the instigation of the inflammatory process. DAMP, Damage-associated molecular pattern molecules TLR. Toll-like receptors; NADPH, nicotinamide adenine dinucleotide phosphate oxidase; RAGE, receptor of advanced glycation end-products; CD, cluster of differentiation. The major inflammatory pathway is marked in red.