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诱导的mtDNA释放通过cGAS-STING信号在肝细胞中促进炎症反应
Hang Pan1, Qian Su1, Panjing Hong1
1College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Pesticide biochemistry and physiology
|October 30, 2024
概括
三氧化物 (ATO) 暴露会触发肝细胞中的线粒体DNA (mtDNA) 释放,激活cGAS-STING通路并引起炎症. 抑制这种途径可以减少ATO诱导的肝损伤.
科学领域:
- 毒理学 毒理学 毒理学
- 免疫学 免疫学 免疫学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 化合物,特别是三氧化物 (ATO),是已知的肝毒素.
- 在ATO诱导的肝损伤中,循环GMP-AMP合成酶 (cGAS) 刺激干扰素基因 (STING) 途径的作用仍然未被探索.
研究的目的:
- 为了研究炎症反应与三氧化物诱导的肝毒性在的参与.
- 阐明通过cGAS-STING信号通路调解的ATO诱导肝损伤的机制.
主要方法:
- 肝细胞暴露于三氧化 (ATO).
- 评估线粒体DNA (mtDNA) 泄漏和cGAS-STING通路的激活 (测量cGAS,STING,TBK1,IRF7mRNA和蛋白质).
- 对I型干扰素和NF-κB信号通路的评估,包括促炎性细胞因子 (TNF-α,IL-6,IL-1β).
- 用乙基化物 (EtBr) 干预mtDNA清除和H-151抑制cGAS-STING通路.
主要成果:
- 暴露于ATO导致mtDNA泄漏到肝细胞的细胞质中.
- 这种泄漏激活了cGAS-STING通路,提高了关键信号分子的调节,并启动了I型干扰素反应.
- 激活STING导致NF-κB通路的激活,并增加了促炎性细胞因子的表达.
- mtDNA清除和cGAS-STING通路的抑制都逆转了ATO诱导的炎症反应.
结论:
- 肝细胞在ATO暴露后通过mtDNA-cGAS-STING通路激活先天免疫和炎症反应.
- 这种途径在ATO诱导的肝毒性机制中起着重要作用.
- 调查结果为了解ATO毒性和开发潜在干预措施提供了关键的见解.
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