Hepcidin and iron regulatory proteins coordinately regulate ferroportin 1 expression in the brain of mice.

Iron plays an essential role in various cellular metabolic processes of the body. Maintenance of cellular iron homeostasis is particularly important for keeping the normal functions of the cells. Ferroportin 1 (FPN1) is the currently only known iron exporter on the cell membrane. It has been indicated that the regulation of FPN1 in response to the alteration of iron level mainly involves two processes, posttranscriptional repression by iron regulatory proteins (IRPs) and posttranslational degradation by hepcidin, the major iron-sensing hormone. However, whether there is any communication between the two types of regulations or which one plays dominant role has not been reported. In our study with IRP2-/- mice, we found that knockout of IRP2 increased FPN1 expression in the cerebral cortex of IRP2-/- mice, whereas the upregulation of FPN1 was more significant in IRP1/IRP2 dual knockdown fibroblasts. Interestingly, we found that the knockout of IRP2 severely affected the regulation effect of hepcidin on FPN1 in mouse brain. FPN1 level decreased dramatically in the brain of wild-type mice injected with hepcidin, but it did not decrease much in IRP2 knockout mice. Further investigation disclosed that the compromised hepcidin-FPN1 regulation in IRP2-/- cells was directly dependent on the existence of iron-responsive element (IRE) in FPN1 messenger RNA. These results indicate that IRPs and hepcidin coordinately regulate the FPN1 level in mice. This study will provide a more comprehensive understanding of the regulatory mechanisms of FPN1 expression.

Iron overload induced by IRP2 gene knockout aggravates symptoms of Parkinson's disease.

Parkinson's disease (PD) is accompanied by iron overload in the brain. However, whether iron accumulation is the cause or effect of PD is still unknown. Iron regulatory protein 2 (IRP2) plays a critical role in keeping iron homeostasis, and our previous data showed that the deletion of the IRP2 gene caused iron deposits in organs of mice. Therefore, we further investigated the role of iron overload induced by IRP2 gene deletion in the development of the MPTP-induced PD mouse model in vivo, and the underlying regulatory mechanisms in primary cultures of astrocytes in vitro. Data from neurobehavioral, immunohistochemistry, TUNEL and Elisa studies showed that MPTP treatment enhanced the symptoms of PD in vivo, increased cell apoptosis and decreased dopamine levels in IRP2-/- mice. In addition, the expression of L-ferritin and iron contents increased significantly in the substantia nigra (SN) of IRP2-/- mice. Moreover, MPTP treatment significantly increased the expression of DMT1 (-IRE) and decreased the expression of TfR1 in IRP2-/- mice. Further investigations with primary cultures of astrocytes from IRP2-/- mice showed that MPP+ increased the expression of L-ferritin and DMT1 (-IRE), and decreased the expression of TfR1. Our results demonstrated that IRP2 gene deletion induced iron accumulation in the SN, which exacerbated the neuronal apoptosis and Parkinsonism symptoms. At the same time, IRP2 gene deletion increased the iron contents in astrocytes around neurons, which further decreased their protection for neurons and increased the cell apoptosis, ultimately forming a vicious cycle that leads to the onset and progression of PD.

Astrocyte hepcidin is a key factor in LPS-induced neuronal apoptosis.

Inflammatory responses involving microglia and astrocytes contribute to the pathogenesis of neurodegenerative diseases (NDs). In addition, inflammation is tightly linked to iron metabolism dysregulation. However, it is not clear whether the brain inflammation-induced iron metabolism dysregulation contributes to the NDs pathogenesis. Herein, we demonstrate that the expression of the systemic iron regulatory hormone, hepcidin, is induced by lipopolysaccharide (LPS) through the IL-6/STAT3 pathway in the cortex and hippocampus. In this paradigm, activated glial cells are the source of IL-6, which was essential in the iron overload-activated apoptosis of neurons. Disrupting astrocyte hepcidin expression prevented the apoptosis of neurons, which were able to maintain levels of FPN1 adequate to avoid iron accumulation. Together, our data are consistent with a model whereby inflammation initiates an intercellular signaling cascade in which activated microglia, through IL-6 signaling, stimulate astrocytes to release hepcidin which, in turn, signals to neurons, via hepcidin, to prevent their iron release. Such a pathway is relevant to NDs in that it links inflammation, microglia and astrocytes to neuronal damage.