Iron potentiates microglial interleukin-1β secretion induced by amyloid-β.
Iron potentiates microglial interleukin-1β secretion induced by amyloid-β.
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DOI：
10.1111/jnc.14906
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发表时间：
2020-07
影响因子：
4.7
通讯作者：
Wessling-Resnick M
中科院分区：
文献类型：
--
作者：
Nnah IC;Lee CH;Wessling-Resnick M
阿尔茨海默病（Alzheimer's disease，AD）是以β淀粉样蛋白（amyloid-beta，Aβ）老年斑在患者脑组织中的积聚为特征的疾病。在AD患者和AD动物模型的脑脊液中发现促炎细胞因子白细胞介素-1 β（IL-1β）水平升高。在AD小鼠模型和AD患者死后脑组织中，聚集在淀粉样斑块周围的小胶质细胞中已发现IL-1β表达增加和铁积累。本研究的目的是确定Aβ对小胶质细胞分泌IL-1β的影响，以及铁状态是否影响这种促炎信号线索。为了实现这一目标，将永生化小胶质细胞（IMG）与Aβ一起孵育，添加或不添加铁。qRT-PCR和Western blot分析表明，Aβ可诱导IMG细胞表达IL-1β，并促进其生物合成。通过ELISA测定，这些小胶质细胞以半胱天冬酶-1依赖性方式分泌成熟形式的IL-1β。如通过这些测定所测量的，将IMG细胞与铁一起孵育引起更大的促炎反应。抑制铁转运蛋白DMT 1可保护IMG细胞免受Aβ诱导的炎症。FAC对Aβ诱导的IL-1β诱导的增强作用也被ROS抑制剂拮抗，这支持了DMT 1介导的铁负荷和随后的细胞ROS增加有助于Aβ在小胶质细胞中的炎症作用的观点。免疫印迹和免疫荧光显微镜数据表明，铁的存在增强了Aβ激活NF-κB信号，促进IL-1β的合成。这些结果支持了Aβ通过激活小胶质细胞中的NF-κB信号刺激IL-1β表达的假设。最重要的是，铁似乎加剧了Aβ的促炎作用，从而增加IL-1β水平，这很可能是通过ROS产生。由于IL-1β促进神经元变性，这些结果表明铁状态可以通过改变这种细胞因子的产生而深刻地影响AD的发病机制。
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) senile plaques in patients’ brain tissues. Elevated levels of the pro-inflammatory cytokine interleukin-1beta (IL-1β) have been identified in cerebrospinal fluid of living AD patients and in animal models of AD. Increased expression of IL-1β and the accumulation of iron have been identified in microglial cells that cluster around amyloid plaques in AD mouse models and post-mortem brain tissues of AD patients. The goals of this study were to determine the effects of Aβ on the secretion of IL-1β by microglial cells and whether iron status influences this pro-inflammatory signaling cue. To accomplish this goal, immortalized microglial (IMG) cells were incubated with Aβ with or without the addition of iron. qRT-PCR and Western blot analyses showed that Aβ induces the expression and biosynthesis of IL-1β by IMG cells. These microglial cells secrete the mature form of IL-1β in a caspase-1 dependent manner as determined by ELISA. Incubation of IMG cells with iron provoked a greater pro-inflammatory response as measured by these assays. Inhibition of the iron transporter DMT1 protected IMG cells against Aβ-induced inflammation. Potentiation of Aβ-elicited IL-1β induction by FAC was also antagonized by ROS inhibitors, supporting the notion that DMT1-mediated iron loading and a subsequent increase in cellular ROS contribute to the inflammatory effects of Aβ in microglia. Immunoblots and immunofluorescence microscopy data indicated that the presence of iron enhances Aβ activation of NF-κB signaling to promote synthesis of IL-1β. These results support the hypothesis that Aβ stimulates IL-1β expression by activating NF-κB signaling in microglia cells. Most importantly, iron appears to exacerbate the pro-inflammatory effects of Aβ to increase IL-1β levels, most likely through ROS generation. Because IL-1β promotes neuronal degeneration, these results suggest that iron status can profoundly influence the pathogenesis of AD by altering production of this cytokine.
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