School of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, China.
School of Public Health, Yangzhou University, Yangzhou 225000, China.
Ecotoxicol Environ Saf. 2024 Oct 15;285:117085. doi: 10.1016/j.ecoenv.2024.117085. Epub 2024 Sep 24.
Copper, a vital mineral nutrient, possesses redox qualities that make it both beneficial and toxic to organisms. Excessive environmental copper exposure can result in neurological damage and cognitive decline in humans. Astrocytes, the predominant glial cells in the brain, are particularly vulnerable to pollutants, but the mechanism of copper-induced damage to astrocytes remains elusive. The aim of this study was to determine the role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in initiating NLRP3 inflammasome-induced astrocyte pyroptosis and chronic inflammation under conditions of copper overload. Our findings indicated that copper exposure elevated mitochondrial ROS (mtROS) levels, resulting in mitochondrial damage in astrocytes. This damage caused the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cGAS-STING pathway. This activation resulted in interactions between STING and NLRP3 proteins, facilitating the assembly of the NLRP3 inflammasome and inducing pyroptosis. Furthermore, depletion of mtROS mitigated copper-induced mitochondrial damage in astrocytes and reduced mtDNA leakage. Pharmacological inhibition of STING or STING transfection further reversed copper-induced pyroptosis and the inflammatory response. In conclusion, this study demonstrated that the leakage of mtDNA into the cytoplasm and the subsequent activation of the cGAS-STING-NLRP3 pathway may be potential mechanisms underlying copper-induced pyroptosis in astrocytes. These findings provided new insights into the toxicity of copper.
铜是一种重要的矿物质营养元素，具有氧化还原特性，对生物体既有益又有毒。过量的环境铜暴露会导致人类的神经损伤和认知能力下降。星形胶质细胞是大脑中主要的神经胶质细胞，对污染物特别敏感，但铜诱导星形胶质细胞损伤的机制仍不清楚。本研究旨在确定环鸟苷酸-腺苷酸合酶-干扰素基因刺激物（cGAS-STING）通路在铜过载条件下，起始 NOD 样受体热蛋白结构域 3（NLRP3）炎性体诱导的星形胶质细胞细胞焦亡和慢性炎症中的作用。我们的研究结果表明，铜暴露会升高线粒体活性氧（mtROS）水平，导致星形胶质细胞中的线粒体损伤。这种损伤导致线粒体 DNA（mtDNA）释放到细胞质中，随后激活 cGAS-STING 通路。这种激活导致 STING 和 NLRP3 蛋白之间的相互作用，促进 NLRP3 炎性体的组装并诱导细胞焦亡。此外，mtROS 的耗竭减轻了铜诱导的星形胶质细胞中线粒体损伤和 mtDNA 泄漏。STING 的药理学抑制或 STING 转染进一步逆转了铜诱导的细胞焦亡和炎症反应。总之，本研究表明，mtDNA 向细胞质的漏出以及随后 cGAS-STING-NLRP3 通路的激活可能是铜诱导星形胶质细胞细胞焦亡的潜在机制。这些发现为铜的毒性提供了新的见解。
