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 (α-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 α-syn. Our results showed that recombinant α-syn (1 μg/ml and 5 μg/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-α (TNF-α), interleukin (IL)-1β, and IL-6 exhibited up-regulated mRNA levels in 5 μg/ml α-syn-treated astrocytes. TNF-α release was increased, indicating that inflammatory responses were triggered in these cells. Pretreatment with the iron-overload reagent ferric ammonium citrate (FAC, 100 μmol/L) for 24 h had no effects on mRNA levels and release of proinflammatory cytokines. Inflammatory responses triggered by α-syn were not affected by iron overload. The iron chelator desferrioxamine (DFO, 100 μmol/L) exerted suppressive effects on TNF-α mRNA levels, although no change was observed for TNF-α release. Hepcidin mRNA levels were down-regulated significantly in astrocytes co-treated with FAC and α-syn, although independent treatment with either FAC or α-syn did not alter hepcidin levels. In contrast, hepcidin mRNA levels were up-regulated in DFO and α-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 α-syn, hepcidin-to-ferritin levels were indicative of modulatory effects in α-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 α-syn.
Highlights
Parkinson’s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in the substantia nigra (SN), resulting in motor symptoms including rigidity, postural instability, tremor at rest, and bradykinesia
The results showed that there were no changes in any of these protein or hepcidin mRNA levels (Figures 1, 4), suggesting that neither 1 μg/ml nor 5 μg/ml α-syn had any effects on the iron transporting or iron regulatory components of astrocytes
The results showed that treatment with 5 μg/ml, but not 1 μg/ml αsyn, induced a significant increase in tumor necrosis factor-α (TNF-α) mRNA and IL-1β mRNA expression, indicating that inflammatory responses were triggered in these cells
Summary
Parkinson’s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in the substantia nigra (SN), resulting in motor symptoms including rigidity, postural instability, tremor at rest, and bradykinesia. In addition to the presence of LBs in the most affected SN, α-syn aggregates have been found in other brain regions, including the locus coeruleus, nucleus basalis of Meynert, hypothalamus, cerebral cortex, and cranial nerve motor nuclei, as well as in the central and peripheral divisions of the autonomic nervous system (Spillantini et al, 1997; Braak et al, 2010) Based on these findings, the prion hypothesis suggests that in the brain, α-syn released from degenerating neurons into extracellular spaces is taken up by neighboring neurons and non-neuronal cells (VolpicelliDaley et al, 2011; Luk et al, 2012; Paumier et al, 2015; Brundin and Melki, 2017). Amyloid-β (Aβ), another disease-associated misfolded protein was shown to induce inflammatory responses in astrocytes both in vivo and in vitro (Urrutia et al, 2013)
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