Hepcidin-to-Ferritin Ratio Is Decreased in Astrocytes With Extracellular Alpha-Synuclein and Iron Exposure
Hepcidin-to-Ferritin Ratio Is Decreased in Astrocytes With Extracellular Alpha-Synuclein and Iron Exposure
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细胞外α-突触核蛋白和铁暴露导致星形胶质细胞中铁调素与铁蛋白的比率降低
DOI：
10.3389/fncel.2020.00047
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发表时间：
2020-03-10
影响因子：
5.3
通讯作者：
Xie, Junxia
中科院分区：
文献类型：
--
作者：
Cui, Juntao;Guo, Xinli;Xie, Junxia
星形胶质细胞是中枢神经系统中数量最多的神经胶质细胞。作为神经血管单位不可或缺的成分，它们参与炎症反应和疾病相关过程。α-突触核蛋白（α-syn）由神经元释放到细胞外空间，并可被相邻的星形胶质细胞内化，从而激活神经胶质细胞以诱导神经炎症。我们感兴趣的是星形胶质细胞介导的神经炎症是否受到细胞内铁状态和细胞外α-syn的调节。我们的研究结果表明，重组α-syn（1 μ g/ml和5 μ g/ml）处理24小时不影响铁转运蛋白二价金属转运蛋白1（DMT 1）和膜铁转运蛋白1（FPN 1）的表达，也不影响铁调节蛋白（IRP）1或IRP 2的表达。几种促炎细胞因子，包括肿瘤坏死因子-α（TNF-α），白细胞介素（IL）-1 β和IL-6在5 μ g/ml α-syn处理的星形胶质细胞中表现出上调的mRNA水平。TNF-α释放增加，表明这些细胞中触发了炎症反应。铁超载试剂柠檬酸铁铵（FAC，100 μ mol/L）预处理24 h对促炎细胞因子的mRNA水平和释放没有影响。由alpha-syn引发的炎症反应不受铁超载的影响。铁螯合剂去铁胺（DFO，100 μ mol/L）对TNF-α mRNA水平产生抑制作用，尽管没有观察到TNF-α释放的变化。在用FAC和α-syn共处理的星形胶质细胞中，铁调素mRNA水平显著下调，尽管用FAC或α-syn单独处理不改变铁调素水平。相反，铁调素mRNA水平在DFO和α-syn共处理的细胞中上调。正如预期的那样，铁蛋白蛋白水平分别用FAC或DFO处理上调或下调。在α-syn介导的铁蛋白上调后，铁调素-铁蛋白水平指示了α-syn处理的具有改变的铁状态的星形胶质细胞中的调节作用。因此，我们提出铁调素与铁蛋白的比率指示在经历铁和细胞外α-syn的原代培养的星形胶质细胞中的有害反应。
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 (alpha-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 alpha-syn. Our results showed that recombinant alpha-syn (1 mu g/ml and 5 mu 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-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 exhibited up-regulated mRNA levels in 5 mu g/ml alpha-syn-treated astrocytes. TNF-alpha release was increased, indicating that inflammatory responses were triggered in these cells. Pretreatment with the iron-overload reagent ferric ammonium citrate (FAC, 100 mu mol/L) for 24 h had no effects on mRNA levels and release of proinflammatory cytokines. Inflammatory responses triggered by alpha-syn were not affected by iron overload. The iron chelator desferrioxamine (DFO, 100 mu mol/L) exerted suppressive effects on TNF-alpha mRNA levels, although no change was observed for TNF-alpha release. Hepcidin mRNA levels were down-regulated significantly in astrocytes co-treated with FAC and alpha-syn, although independent treatment with either FAC or alpha-syn did not alter hepcidin levels. In contrast, hepcidin mRNA levels were up-regulated in DFO and alpha-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 alpha-syn, hepcidin-to-ferritin levels were indicative of modulatory effects in alpha-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 alpha-syn.