Urrutia Pamela J, Bórquez Daniel A, Núñez Marco Tulio
Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile.
Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, 8370007 Santiago, Chile.
Antioxidants (Basel). 2021 Jan 6;10(1):61. doi: 10.3390/antiox10010061.
Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood-brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD.
铁蓄积和神经炎症是在包括阿尔茨海默病（AD）和帕金森病（PD）在内的几种神经退行性疾病中发现的病理状况。铁与炎症以双向关系相互交织，其中铁改变小胶质细胞和浸润性巨噬细胞的炎症表型，反过来，这些细胞分泌可扩散的介质，重塑神经元铁稳态并调节铁进入大脑。分泌的炎症介质包括细胞因子和活性氧/氮物种（ROS/RNS），特别是铁调素和一氧化氮（·NO）。铁调素是一种小阳离子肽，在调节全身铁稳态中起核心作用。铁调素也存在于脑脊液（CSF）中，它可以通过与铁输出蛋白铁转运蛋白1（Fpn1）结合，减少神经元中的铁输出，并减少铁通过血脑屏障（BBB）的进入。同样，·NO选择性地将胞质乌头酸酶（c-乌头酸酶）转化为铁调节蛋白1（IRP1），IRP1通过与铁相关蛋白mRNA中位于的铁反应元件（IRE）结合来调节细胞铁稳态。一氧化氮激活的IRP1在神经炎症期间会损害细胞铁稳态，引发铁蓄积，尤其是在线粒体中，导致神经元死亡。在这篇综述中，我们将总结将神经炎症和铁蓄积联系起来的研究结果，并支持它们在AD和PD中观察到的神经退行性过程中的因果关联。
