Wang Ke, Yao Yong, Zhu Xue, Zhang Kai, Zhou Fanfan, Zhu Ling
Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu Province, People's Republic of China.
Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, Jiangsu Province, People's Republic of China.
J Biochem Mol Toxicol. 2017 Jun;31(6). doi: 10.1002/jbt.21887. Epub 2016 Dec 22.
Amyloid β (Aβ)-induced chronic inflammation is believed to be a key pathogenic process in early-stage age-related macular degeneration (AMD). Nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation triggered by Aβ is responsible for retinal pigment epithelium (RPE) dysfunction in the onset of AMD; however, the detailed molecular mechanism remains unclear. In this study, we investigated the involvement of NADPH oxidase- and mitochondria-derived reactive oxygen species (ROS) in the process of Aβ -induced NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. The results showed that Aβ could induce excessive ROS generation, MAPK/NF-κB signaling activation and subsequently NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. Furthermore, the inductive effect of Aβ on NLRP3 inflammasome activation was mediated in a manner dependent on NADPH oxidase- and mitochondria-derived ROS. Our findings may provide a novel insight into the molecular mechanism by which Aβ contributes to the early-stage AMD.
淀粉样β（Aβ）诱导的慢性炎症被认为是早期年龄相关性黄斑变性（AMD）的关键致病过程。由Aβ触发的核苷酸寡聚化结构域（NOD）样受体家族含pyrin结构域3（NLRP3）炎性小体激活，在AMD发病过程中导致视网膜色素上皮（RPE）功能障碍；然而，具体分子机制仍不清楚。在本研究中，我们调查了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶和线粒体衍生的活性氧（ROS）在Aβ诱导的脂多糖（LPS）预处理的ARPE - 19细胞中NLRP3炎性小体激活过程中的作用。结果表明，Aβ可在LPS预处理的ARPE - 19细胞中诱导过量ROS生成、丝裂原活化蛋白激酶/核因子κB（MAPK/NF-κB）信号激活以及随后的NLRP3炎性小体激活。此外，Aβ对NLRP3炎性小体激活的诱导作用是以依赖NADPH氧化酶和线粒体衍生的ROS的方式介导的。我们的发现可能为Aβ导致早期AMD的分子机制提供新的见解。
