Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation
Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation
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DOI：
10.1074/jbc.m116.769240
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发表时间：
2017-03-01
影响因子：
4.8
通讯作者：
Kondapalli, Kalyan C.
中科院分区：
文献类型：
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作者：
Beydoun, Rami;Hamood, Mohamed A.;Kondapalli, Kalyan C.
铁对于大脑功能至关重要，大脑中铁稳态的丧失与神经系统疾病有关，从罕见综合症到更常见的疾病，如帕金森病和阿尔茨海默病。铁进入大脑受到血脑屏障（BBB）的调节。人们对调节这种运输的分子机制知之甚少。使用 BBB 的体外模型，我们确定 NHE9（一种内体阳离子/质子交换器）作为该系统的新型调节剂。构成 BBB 的人脑微血管内皮细胞 (hBMVEC) 通过来自鞘星形胶质细胞的旁分泌信号接收脑铁状态信息。在 hBMVEC 中，我们发现 NHE9 表达在由缺铁星形胶质细胞的旁分泌信号引发的生理反应中很早就上调。在没有外部信号的情况下，hBMVEC 中 NHE9 的异位表达会诱导转铁蛋白受体 (TfR) 上调和铁蛋白下调，从而导致铁摄取增加。从机制上讲，我们证明 NHE9 定位于 hBMVEC 中的内体回收，从而提高内体 pH 值。随后内体腔的碱化增加了 TfR 向 hBMVEC 膜的易位。此前研究表明，膜上的 TfR 可促进依赖于回收和不依赖于回收的铁的吸收。我们提出，NHE9 通过响应旁分泌信号微调内体 pH 值来调节 hBMVEC 中 TfR 依赖性、循环独立的铁吸收，因此是 BBB 铁动员途径的重要调节因子。
Iron is essential for brain function, with loss of iron homeo-stasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.