Luo Daopeng, Sun Baofei, Wang Wenjuan, Zhang Aihua
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 561113, China.
Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases, Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 561113, China.
Biol Trace Elem Res. 2024 Dec 18. doi: 10.1007/s12011-024-04475-z.
Arsenic is a detrimental environmental toxicant linked to neurological damage; however, the mechanisms involved remain incompletely understood. Chronic proinflammatory responses are thought to play a central role in arsenic-induced neurotoxicity. Astrocytes, which are the predominant glial cells in the central nervous system (CNS), release significant amounts of proinflammatory cytokines upon overactivation. However, the molecular mechanisms driving this response remain to be elucidated. This study aimed to elucidate the mechanisms underlying arsenic-induced astrocyte activation and the subsequent neuronal damage, both in vivo and in vitro. In a rat model of arsenic exposure, significant neuropathological damage was detected in the CA3 region of the hippocampus. Specifically, markers of astrocyte activation, such as glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS), as well as the inflammatory cytokine interleukin (IL)-1β, were significantly upregulated, and apoptosis was markedly increased, indicating neurotoxic damage. Furthermore, in vitro experiments revealed that arsenic exposure induced substantial upregulation of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), GFAP, iNOS, and IL-1β in astrocytes, accompanied by an increase in IL-1β secretion into the culture supernatant. In addition, co-culturing neurons with conditioned medium from arsenic-exposed astrocytes resulted in significant neuronal apoptosis. Importantly, the cGAS-STING pathway inhibitor H-151 effectively suppressed the arsenic-induced astrocyte activation and IL-1β secretion, while also reducing neuronal apoptosis in the conditioned medium. Collectively, these results indicate that arsenic exposure activates the cGAS-STING signaling pathway in astrocytes, enhancing proinflammatory activation and IL-1β expression, which in turn mediates neuronal apoptosis, representing a critical mechanism underlying arsenic-induced neurotoxicity.
砷是一种有害的环境毒物，与神经损伤有关；然而，其涉及的机制仍未完全了解。慢性促炎反应被认为在砷诱导的神经毒性中起核心作用。星形胶质细胞是中枢神经系统（CNS）中主要的胶质细胞，过度激活时会释放大量促炎细胞因子。然而，驱动这种反应的分子机制仍有待阐明。本研究旨在阐明砷诱导星形胶质细胞激活及随后神经元损伤的体内和体外机制。在砷暴露的大鼠模型中，在海马体的CA3区域检测到明显的神经病理损伤。具体而言，星形胶质细胞激活的标志物，如胶质纤维酸性蛋白（GFAP）和诱导型一氧化氮合酶（iNOS），以及炎性细胞因子白细胞介素（IL）-1β显著上调，且细胞凋亡明显增加，表明存在神经毒性损伤。此外，体外实验表明，砷暴露诱导星形胶质细胞中环磷酸鸟苷-腺苷酸合酶（cGAS）、干扰素基因刺激因子（STING）、GFAP、iNOS和IL-1β大量上调，同时培养上清液中IL-1β的分泌增加。此外，将神经元与砷暴露星形胶质细胞的条件培养基共培养导致显著的神经元凋亡。重要的是，cGAS-STING通路抑制剂H-151有效抑制了砷诱导的星形胶质细胞激活和IL-1β分泌，同时也减少了条件培养基中的神经元凋亡。总体而言，这些结果表明，砷暴露激活了星形胶质细胞中的cGAS-STING信号通路，增强了促炎激活和IL-1β表达，进而介导神经元凋亡，这是砷诱导神经毒性的关键机制。
