Neurodegeneration is associated with inflammation and mismanaged iron homeostasis, leading to increased concentration of non‐transferrin‐bound iron (NTBI) in the brain. NTBI can be taken up by cells expressing Zrt‐, Irt‐like protein‐14 (ZIP14), which is regulated by iron overload and pro‐inflammatory cytokines, for example, interleukin‐1β (IL‐1β) and IL‐6. Here, we focus on the astrocytic involvement and regulation of ZIP14 in an experimental model of chronic neurodegeneration with inflammation and iron overload. Rats were unilaterally injected with ibotenic acid in striatum resulting in excitotoxicity‐induced neuronal loss in substantia nigra pars reticulata (SNpr). ZIP14 expression was measured in SNpr using immunohistochemistry, western blotting, and RT‐qPCR. Cultures of primary astrocytes were examined for Zip14 mRNA expression after stimulation with ferric ammonium citrate (FAC), IL‐6, or IL‐1β. To study the involvement of ZIP14 in astrocytic iron uptake, uptake of ⁵⁹Fe was investigated after treatment with IL‐1β and siRNA‐mediated ZIP14 knockdown. In the lesioned SNpr, reactive astrocytes, but not microglia, revealed increased ZIP14 expression with a main confinement to cell bodies and cellular processes. In astrocyte cultures, FAC and IL‐1β stimulation increased Zip14 expression and IL‐1β stimulation increased uptake of ⁵⁹Fe. Increased ⁵⁹Fe uptake was also observed after siRNA‐mediated ZIP14 knockdown suggesting that lowering of ZIP14 impaired the balance between astrocytic uptake and export of iron. We conclude that astrocytes increase ZIP14 expression in response to inflammation and iron exposure and that ZIP14 seems pertinent for iron uptake in astrocytes and plays a role for a balanced astrocytic iron homeostasis.

中文翻译：

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ZIP14 (SLC39A14) 的星形胶质细胞表达是铁过载慢性神经变性炎症反应的一部分。

神经变性与炎症和铁稳态管理不当有关，导致大脑中非转铁蛋白结合铁 (NTBI) 的浓度增加。NTBI 可以被表达 Zrt-、Irt 样蛋白-14 (ZIP14) 的细胞吸收，ZIP14 受铁过载和促炎细胞因子的调节，例如白细胞介素-1β (IL-1β) 和 IL-6。在这里，我们专注于 ZIP14 在具有炎症和铁过载的慢性神经变性实验模型中的星形胶质细胞参与和调节。在大鼠的纹状体中单方面注射了石竹酸，导致黑质网状部 (SNpr) 中兴奋性毒性诱导的神经元丢失。使用免疫组织化学、蛋白质印迹和 RT-qPCR 在 SNpr 中测量 ZIP14 表达。检查原代星形胶质细胞培养物中的Zip14用柠檬酸铁铵 (FAC)、IL-6 或 IL-1β 刺激后的 mRNA 表达。为了研究 ZIP14 参与星形胶质细胞铁摄取，在用 IL-1β 和 siRNA 介导的 ZIP14 敲低处理后研究了⁵⁹ Fe 的摄取。在受损的 SNpr 中，反应性星形胶质细胞而非小胶质细胞显示 ZIP14 表达增加，主要限制于细胞体和细胞过程。在星形胶质细胞培养物中，FAC 和 IL-1β 刺激增加了Zip14表达，IL-1β 刺激增加了⁵⁹ Fe 的摄取。增加⁵⁹在 siRNA 介导的 ZIP14 敲低后也观察到铁摄取，这表明 ZIP14 的降低损害了星形胶质细胞摄取和铁输出之间的平衡。我们得出结论，星形胶质细胞响应炎症和铁暴露而增加 ZIP14 表达，并且 ZIP14 似乎与星形胶质细胞的铁摄取有关，并在平衡星形胶质细胞铁稳态中发挥作用。