AUTHOR=Cui Juntao , Guo Xinli , Li Qijun , Song Ning , Xie Junxia 

TITLE=Hepcidin-to-Ferritin Ratio Is Decreased in Astrocytes With Extracellular Alpha-Synuclein and Iron Exposure

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.00047

DOI=10.3389/fncel.2020.00047

ISSN=1662-5102

ABSTRACT=Astrocytes are the most abundant glial cells in the central nervous system. As indispensable element of the neurovascular unit, astrocytes were involved in the inflammatory response and disease-related processes. In the extracellular space, alpha-synuclein (α-syn) released by neurons, and adjacent astrocytes can internalize the transmitted α-syn, the latter activating glial cells to induce neuroinflammation. We are interested in whether astrocytes-mediated neuroinflammation was modulated by intracellular status iron and extracellular α-syn. The results showed that recombinant α-syn (1 μg/ml and 5 μg/ml) treatment for 24 h did not affect the expression of iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), as well as iron regulatory protein (IRP) 1 and IRP2. Several proinflammatory cytokines, e.g. tumor necrosis factor-α (TNF-α), interleukin (IL) 1β and IL-6 were up-regulated on mRNA levels in 5 μg/ml α-syn treated astrocytes, together with an increased release of TNF-α, indicating the inflammatory responses were triggered in these cells. Pretreatments of iron-overload reagent ferric ammonium citrate (FAC, 100 μmol/L) for 24h have no effects on the mRNA levels and release of these proinflammatory cytokines, also have no effects on α-syn triggered responses. Iron chelator desferrioxamine (DFO, 100 μmol/L) exerted suppressive effects on TNF-α mRNA levels, although no change was observed on TNF-α release. Hepcidin mRNA levels was down-regulated significantly in astrocytes co-treated with FAC and α-syn, although neither FAC or α-syn could regulate hepcidin levels separately. On the contrary, hepcidin mRNA levels was up-regulated in DFO/α-syn treated cells, in parallel with an increase IL-6 mRNA levels. As expected, ferritin protein levels were up-regulated or down-regulated with FAC or DFO treatment. Upon the up-regulation of ferritin exerted by α-syn, hepcidin to ferritin levels was more indicative for the modulatory effects in α-syn-treated astrocytes with altered iron status. Therefore, we proposed hepcidin to ferritin ratio was more indicative as a detrimental response in primary cultured astrocytes experiencing iron and extracellular α-syn.