cGAS和DDX41-STING介导的固有免疫在细胞间传播，以促进SOD1肌萎缩侧索硬化模型中的神经炎症。
cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model.
作者信息
Tan Hong Yien, Yong Yean Kong, Xue Yuan Chao, Liu Huitao, Furihata Tomomi, Shankar Esaki Muthu, Ng Chen Seng
机构信息
Laboratory Centre, Xiamen University Malaysia, Sepang, Selangor, Malaysia.
School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Selangor, Malaysia.
出版信息
iScience. 2022 May 13;25(6):104404. doi: 10.1016/j.isci.2022.104404. eCollection 2022 Jun 17.
Neuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1)-causing ALS results in mitochondrial damage, thus triggering the release of mtDNA and an RNA:DNA hybrid into the cytosol in an mPTP-independent manner to activate IRF3- and IFNAR-dependent type I interferon (IFN-I) and interferon-stimulating genes. The neuronal hyper-IFN-I and pro-inflammatory responses triggered in ALS-SOD1 were sufficiently robust to cause a strong physiological outcome and . cGAS/DDX41-STING-signaling is amplified in bystander cells through inter-neuronal gap junctions. Our results highlight the importance of a common DNA-sensing pathway between SOD1 and TDP-43 in influencing the progression of ALS.
神经炎症会加剧超氧化物歧化酶1（SOD1）驱动的肌萎缩侧索硬化症（ALS）的进展，尽管其潜在机制在很大程度上仍不清楚。在此，我们证明，导致ALS的错误折叠的SOD1（突变型SOD1）会导致线粒体损伤，从而以一种不依赖线粒体通透性转换孔（mPTP）的方式触发线粒体DNA（mtDNA）和一种RNA:DNA杂交体释放到细胞质中，以激活依赖干扰素调节因子3（IRF3）和干扰素α受体（IFNAR）的I型干扰素（IFN-I）以及干扰素刺激基因。在ALS-SOD1中触发的神经元过度IFN-I和促炎反应足够强烈，足以导致强烈的生理结果。并且，环鸟苷酸-腺苷酸合成酶（cGAS）/解旋酶DDX41-干扰素基因刺激蛋白（STING）信号通路通过神经元间的缝隙连接在旁观者细胞中被放大。我们的结果突出了SOD1和TDP-43之间共同的DNA传感通路在影响ALS进展中的重要性。
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