Rangarajan P, Karthikeyan A, Lu J, Ling E-A, Dheen S T
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore.
Neuroscience. 2015 Dec 17;311:398-414. doi: 10.1016/j.neuroscience.2015.10.048. Epub 2015 Oct 30.
Microglia are the prime cellular sources of reactive oxygen species (ROS) in the central nervous system (CNS). Chronic activation of microglia has been linked to aging-associated neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) since they produce excessive amounts of ROS for a prolonged duration leading to oxidative stress. The present study was aimed at investigating the expression and role of Sirtuin 3 (Sirt3), a protein deacetylase which is implicated in regulating cellular ROS levels. It has been shown that Sirt3 reduces cellular ROS levels by deacetylating forkhead box O 3a (Foxo3a), a transcription factor which transactivates antioxidant genes, catalase (Cat) and manganese superoxide dismutase (mnSod). In the present study, Sirt3 immunoreactivity was localized in the ameboid microglial cells distributed in the corpus callosum (CC) of the early postnatal rat brain and diminished in the ramified microglial cells in the CC of the adult rat brain. A marked induction of Sirt3 expression was seen in lipopolysaccharide (LPS)-activated microglia in vivo and in vitro as well as in adult rat brains subjected to traumatic brain injury (TBI). Knockdown of Sirt3 in microglia led to an increase in the cellular and mitochondrial ROS and decrease in the expression of antioxidant, mnSod which is indicative of the function of Sirt3 in ROS regulation in microglia. Conversely, Sirt3 overexpression led to increase in the expression of antioxidants Cat and mnSod. Further, increase in the expression and nuclear translocation of Foxo3a was observed following Sirt3 overexpression, suggesting that Sirt3 regulates ROS by inducing the expression of antioxidants via activation of Foxo3a. The above results point to an antioxidant defense mechanism presented by Sirt3 through the activation of Foxo3a, in microglia.
小胶质细胞是中枢神经系统（CNS）中活性氧（ROS）的主要细胞来源。小胶质细胞的慢性激活与衰老相关的神经退行性疾病如阿尔茨海默病（AD）和帕金森病（PD）有关，因为它们会在较长时间内产生过量的ROS，导致氧化应激。本研究旨在调查沉默调节蛋白3（Sirt3）的表达和作用，Sirt3是一种蛋白质脱乙酰酶，与调节细胞ROS水平有关。研究表明，Sirt3通过使叉头框O 3a（Foxo3a）脱乙酰化来降低细胞ROS水平，Foxo3a是一种转录因子，可激活抗氧化基因、过氧化氢酶（Cat）和锰超氧化物歧化酶（mnSod）。在本研究中，Sirt3免疫反应性定位于出生后早期大鼠脑胼胝体（CC）中分布的阿米巴样小胶质细胞中，而在成年大鼠脑CC中的分支状小胶质细胞中则减少。在体内和体外脂多糖（LPS）激活的小胶质细胞以及遭受创伤性脑损伤（TBI）的成年大鼠脑中，均观察到Sirt3表达的显著诱导。小胶质细胞中Sirt3的敲低导致细胞和线粒体ROS增加，以及抗氧化剂mnSod的表达降低，这表明Sirt3在小胶质细胞的ROS调节中发挥作用。相反，Sirt3的过表达导致抗氧化剂Cat和mnSod的表达增加。此外，Sirt3过表达后观察到Foxo3a的表达和核转位增加，表明Sirt3通过激活Foxo3a诱导抗氧化剂的表达来调节ROS。上述结果表明，Sirt3在小胶质细胞中通过激活Foxo3a呈现出一种抗氧化防御机制。
