Li Ke, Yang Xuejiao, Xu Tong, Shi Xu, Xu Shiwen
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113546. doi: 10.1016/j.intimp.2024.113546. Epub 2024 Nov 2.
Silicon dioxide particles (SiO) are a widely used novel material, and SiO that enter the body can accumulate in the spleen and cause spleen injury. Quercetin (Que) has a strong antioxidant activity and can also regulate and improve immune function, but whether Que can improve SiO2-induced spleen injury and its underlying mechanism remain to be explored. Herein, we established a C57BL/6 mice model with SiO exposure (10 mg/kg) and treated with Que (25 mg/kg). We also cultured CTLL-2 cells for in vitro experiments. Studies in vivo and in vitro showed that SiO exposure caused oxidative stress and mitochondrial dynamics disorder, which led to decrease of mitochondrial membrane potential (ΔΨm) and mitochondrial DNA (mtDNA) leakage. mtDNA was recognized by Z-DNA binding protein 1 (ZBP1) in the cytoplasm and increased the expression of ZBP1. This process further promoted the assembly of the ZBP1-mediated PANoptosome, which subsequently induced PANoptosis. Interestingly, supplementation with Que significantly reversed these changes. Specifically, Que mitigated spleen ZBP-1 mediated PANoptosis through preventing mtDNA leakage via regulating nuclear factor erythroid 2-related factor 2/reactive oxygen species/dynamin-related protein 1 (Nrf2/ROS/Drp1) axis. This study enriches the understanding of the toxicological mechanisms of SiO and provides evidence for the protective effects of Que against SiO-induced splenic toxicity.
二氧化硅颗粒（SiO）是一种广泛应用的新型材料，进入体内的SiO会在脾脏中蓄积并导致脾脏损伤。槲皮素（Que）具有较强的抗氧化活性，还能调节和改善免疫功能，但Que是否能改善SiO₂诱导的脾脏损伤及其潜在机制仍有待探索。在此，我们建立了SiO暴露（10 mg/kg）的C57BL/6小鼠模型并用Que（25 mg/kg）进行处理。我们还培养了CTLL-2细胞用于体外实验。体内和体外研究表明，SiO暴露会引起氧化应激和线粒体动力学紊乱，导致线粒体膜电位（ΔΨm）降低和线粒体DNA（mtDNA）泄漏。mtDNA在细胞质中被Z-DNA结合蛋白1（ZBP1）识别并增加ZBP1的表达。这一过程进一步促进了ZBP1介导的PANoptosome的组装，随后诱导PANoptosis。有趣的是，补充Que显著逆转了这些变化。具体而言，Que通过调节核因子红细胞2相关因子2/活性氧/动力相关蛋白1（Nrf2/ROS/Drp1）轴防止mtDNA泄漏，从而减轻脾脏ZBP-1介导的PANoptosis。本研究丰富了对SiO毒理学机制的认识，并为Que对SiO诱导的脾脏毒性的保护作用提供了证据。
