Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, China; Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, China.
Ecotoxicol Environ Saf. 2023 Oct 1;264:115401. doi: 10.1016/j.ecoenv.2023.115401. Epub 2023 Aug 25.
Aluminum is an environmental toxicant whose long-term exposure is closely associated with nervous system impairment. This study mainly investigated neurological impairment induced by subchronic aluminum exposure via activating NLRP3-medicated pyroptosis pathway.
In vivo, Kunming mice were exposed to AlCl (30.3 mg/kg, 101 mg/kg and 303 mg/kg) via drinking water for 3 months, and administered with Rsv (100 mg/kg) by gavage for 1 month. Cognitive impairment was assessed by Morris water maze test, and pathological injury was detected via H&E staining. BBB integrity, pyroptosis and neuroinflammation were evaluated through western blotting and immunofluorescence methods. In vitro, BV2 microglia was treated with AlCl (0.5 mM, 1 mM and 2 mM) to sensitize pyroptosis pathway. The protein interaction was verified by co-immunoprecipitation, and neuronal damage was estimated via a conditioned medium co-culture system with BV2 and TH22 cells.
Our results showed that AlCl induced mice memory disorder, BBB destruction, and pathological injury. Besides, aluminum caused glial activation, sensitized DDX3X-NLRP3 pyroptosis pathway, released cytokines IL-1β and IL-18, initiating neuroinflammation. BV2 microglia treated with AlCl emerged hyperactivation and pyroptotic death, and Ddx3x knockdown inhibited pyroptosis signaling pathway. DDX3X acted as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome and G3BP1 stress granules. Furthermore, aluminum-activated microglia had an adverse effect on co-cultured neurons and destroyed nervous system homeostasis.
Aluminum exposure could induce pyroptosis and neurotoxicity. DDX3X determined live or die via selectively regulating pro-survival stress granules or pro-death NLRP3 inflammasome. Excessive activation of microglia might damage neurons and aggravate nerve injury.
铝是一种环境毒物，其长期暴露与神经系统损伤密切相关。本研究主要通过激活 NLRP3 介导的焦亡途径来研究亚慢性铝暴露引起的神经损伤。
体内实验中，昆明小鼠通过饮用水暴露于 AlCl（30.3mg/kg、101mg/kg 和 303mg/kg）3 个月，并通过灌胃给予 Rsv（100mg/kg）1 个月。通过 Morris 水迷宫试验评估认知障碍，通过 H&E 染色检测病理损伤。通过 Western blot 和免疫荧光方法评估 BBB 完整性、焦亡和神经炎症。体外实验中，用 AlCl（0.5mM、1mM 和 2mM）处理 BV2 小胶质细胞以敏化焦亡途径。通过免疫共沉淀验证蛋白相互作用，并用 BV2 和 TH22 细胞共培养系统评估神经元损伤。
我们的结果表明，AlCl 诱导小鼠记忆障碍、BBB 破坏和病理损伤。此外，铝引起神经胶质细胞激活，敏化 DDX3X-NLRP3 焦亡途径，释放细胞因子 IL-1β 和 IL-18，引发神经炎症。用 AlCl 处理的 BV2 小胶质细胞出现过度激活和焦亡性死亡，DDX3x 敲低抑制焦亡信号通路。DDX3X 通过调节 NLRP3 炎性体和 G3BP1 应激颗粒，在应激细胞中充当生与死的检查点。此外，铝激活的小胶质细胞对共培养的神经元有不良影响，并破坏神经系统内稳态。
铝暴露可诱导焦亡和神经毒性。DDX3X 通过选择性调节促生存应激颗粒或促死亡 NLRP3 炎性体来决定死活。小胶质细胞的过度激活可能会损伤神经元并加重神经损伤。
