Yu Shanshan, Wang Xiaoyan, Lei Shipeng, Chen Xi, Liu Yuanling, Zhou Yunchuan, Zhou Yang, Wu Jingxian, Zhao Yong
Department of Pathology, Chongqing Medical University, 400016 Chongqing, China; Institute of Neuroscience, Chongqing Medical University, 400016 Chongqing, China; Key Laboratory of Neurobiology, Chongqing Medical University, 400016 Chongqing, China.
Department of Respiratory Medicine, Jiangjin Center Hospital, 402260, Chongqing, China.
Neurochem Int. 2015 Mar;82:19-27. doi: 10.1016/j.neuint.2015.01.005. Epub 2015 Jan 22.
Astrocytes appear to be important regulators of the inflammatory events that occur in stroke. Sulfiredoxin-1 (Srxn1), an endogenous antioxidant protein, exhibits neuroprotective effects. Although the mechanism by which Srxn1 negatively regulates oxidative and apoptotic pathways has been extensively characterized, the impact of Srxn1 on inflammation has not been well studied. In this study, we used oxygen-glucose deprivation followed by recovery (OGD/R) and hydrogen peroxide (H2O2) to mimic stress from cerebral ischemic damage on primary cultured astrocytes. We found that knockdown of Srxn1 by two shRNAs resulted in decreased cell viability of astrocytes. Decreased level of Srxn1 also correlated with excessive levels of proinflammatory cytokines and chemokines such as TNF-α, MPO, IL-1β, and IL-6. In addition, Srxn1 appeared to influence the strength of TLR4 signaling pathway; the expression of COX-2, IL-6, and NOS2 were strongly induced by OGD/R and H2O2 in astrocyte cultures with Srxn1-shRNAs. Our results suggested that loss of Srxn1 expression in astrocytes may cause excessive activation of inflammatory responses which contribute to OGD/R- and H2O2-induced cell death. Restoring Srxn1 function by gene therapy and/or pharmacology emerges as a promising strategy for the treatment of stroke and other chronic neurodegenerative diseases.
星形胶质细胞似乎是中风时发生的炎症事件的重要调节因子。硫氧还蛋白-1（Srxn1）是一种内源性抗氧化蛋白，具有神经保护作用。尽管Srxn1负调控氧化和凋亡途径的机制已得到广泛研究，但其对炎症的影响尚未得到充分研究。在本研究中，我们采用氧糖剥夺再灌注（OGD/R）和过氧化氢（H2O2）来模拟原代培养星形胶质细胞受到的脑缺血损伤应激。我们发现，两种短发夹RNA敲低Srxn1导致星形胶质细胞的细胞活力下降。Srxn1水平降低还与促炎细胞因子和趋化因子如肿瘤坏死因子-α、髓过氧化物酶、白细胞介素-1β和白细胞介素-6的过量水平相关。此外，Srxn1似乎影响Toll样受体4（TLR4）信号通路的强度；在转染Srxn1-shRNAs的星形胶质细胞培养物中，OGD/R和H2O2强烈诱导环氧合酶-2（COX-2）、白细胞介素-6和一氧化氮合酶2（NOS2）的表达。我们的结果表明，星形胶质细胞中Srxn1表达缺失可能导致炎症反应过度激活，这促成了OGD/R和H2O2诱导的细胞死亡。通过基因治疗和/或药理学恢复Srxn1功能成为治疗中风和其他慢性神经退行性疾病的一种有前景的策略。
