FIGURE 2.

Iron metabolism in the healthy and traumatically injured brain. (A) Circulating iron (Fe³⁺) passes the blood-brain barrier (BBB) either bound to transferrin or independently, and is then taken up by endothelial cells expressing transferrin receptors via endocytosis. The acidic pH environment of the endosome detaches Fe³⁺ from transferrin and Fe³⁺ is then reduced to Fe²⁺ by ferric reductase (Ward et al., 2014). In the brain, Fe²⁺ is uptaken via DMT1 and distributed amongst astrocytes, neurons, oligodendrocytes, and microglia. Inside these cells, Fe²⁺ is converted to Fe³⁺ and stored by ferritin to prevent oxidative damage (Oshiro et al., 2011). Oligodendrocytes express Tim2 receptor that binds ferritin and iron can be imported through this mechanism, in addition to DMT1. Neurons and microglia can also uptake transferrin-bound iron via transferrin receptors (Ward et al., 2014). Ferrous iron is exported from cells via the iron exporter, ferroportin, which is present on all cell types. Fe²⁺ is rapidly oxidized to Fe³⁺ once outside the cell by ferroxidases such as hephaestin or ceruloplasmin (expressed on astrocytes mainly). Amyloid precursor protein (APP) is expressed on neurons, astrocytes and microglia, and has been found to facilitate iron export in neurons by stabilizing ferroportin (Wong et al., 2014). (B) Injury to the brain/neurovascular unit causes BBB damage, microglia activation, astrogliosis, and eventually damage to neurons and the myelin sheath surrounding axons. Dysregulation of iron metabolism in the brain following TBI can result in the accumulation of redox-active ferrous iron in various brain cells. This is possibly due to alterations in the expression/function of regulatory proteins such as ferroportin, ferritin and ceruloplasmin, which fail to export iron from cells and thereby increases the labile iron pool. Iron accumulation in microgia can cause increased pro-inflammatory cytokine production, and vice versa (Urrutia et al., 2014). Taken together, iron accumulation in the brain can promote oxidative stress that contributes to neurodegeneration.