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

ABSTRACT: Astrocytes are the most abundant glial cells in the central nervous system (CNS). As indispensable elements of the neurovascular unit, they are involved in the inflammatory response and disease-associated processes. Alpha-synuclein (?-syn) is released into the extracellular space by neurons and can be internalized by adjacent astrocytes, which activates glial cells to induce neuroinflammation. We were interested in whether astrocyte-mediated neuroinflammation is modulated by intracellular iron status and extracellular ?-syn. Our results showed that recombinant ?-syn (1 ?g/ml and 5 ?g/ml) treatment for 24 h did not affect the expression of the iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), nor those of iron regulatory protein (IRP) 1 or IRP2. Several proinflammatory cytokines, including tumor necrosis factor-? (TNF-?), interleukin (IL)-1?, and IL-6 exhibited up-regulated mRNA levels in 5 ?g/ml ?-syn-treated astrocytes. TNF-? release was increased, indicating that inflammatory responses were triggered in these cells. Pretreatment with the iron-overload reagent ferric ammonium citrate (FAC, 100 ?mol/L) for 24 h had no effects on mRNA levels and release of proinflammatory cytokines. Inflammatory responses triggered by ?-syn were not affected by iron overload. The iron chelator desferrioxamine (DFO, 100 ?mol/L) exerted suppressive effects on TNF-? mRNA levels, although no change was observed for TNF-? release. Hepcidin mRNA levels were down-regulated significantly in astrocytes co-treated with FAC and ?-syn, although independent treatment with either FAC or ?-syn did not alter hepcidin levels. In contrast, hepcidin mRNA levels were up-regulated in DFO and ?-syn co-treated cells. As expected, ferritin protein levels were up-regulated or down-regulated with FAC or DFO treatment, respectively. Following the up-regulation of ferritin mediated by ?-syn, hepcidin-to-ferritin levels were indicative of modulatory effects in ?-syn-treated astrocytes with altered iron status. Therefore, we propose that the hepcidin-to-ferritin ratio is indicative of a detrimental response in primary cultured astrocytes experiencing iron and extracellular ?-syn.

SUBMITTER: Cui J 

PROVIDER: S-EPMC7075942 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature