Novartis Institutes for BioMedical Research, Novartis Campus, Basel 4002, Switzerland.
Novartis Institutes for BioMedical Research, Novartis Campus, Basel 4002, Switzerland.
Cell Rep. 2021 Nov 9;37(6):109977. doi: 10.1016/j.celrep.2021.109977.
Tumor necrosis factor (TNF) is a key driver of several inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, in which affected tissues show an interferon-stimulated gene signature. Here, we demonstrate that TNF triggers a type-I interferon response that is dependent on the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. We show that TNF inhibits PINK1-mediated mitophagy and leads to altered mitochondrial function and to an increase in cytosolic mtDNA levels. Using cGAS-chromatin immunoprecipitation (ChIP), we demonstrate that cytosolic mtDNA binds to cGAS after TNF treatment. Furthermore, TNF induces a cGAS-STING-dependent transcriptional response that mimics that of macrophages from rheumatoid arthritis patients. Finally, in an inflammatory arthritis mouse model, cGAS deficiency blocked interferon responses and reduced inflammatory cell infiltration and joint swelling. These findings elucidate a molecular mechanism linking TNF to type-I interferon signaling and suggest a potential benefit for therapeutic targeting of cGAS/STING in TNF-driven diseases.
肿瘤坏死因子 (TNF) 是几种炎症性疾病的关键驱动因素，如类风湿性关节炎、炎症性肠病和银屑病，这些疾病的受影响组织表现出干扰素刺激基因特征。在这里，我们证明 TNF 触发依赖于环鸟苷酸-AMP 合酶 (cGAS)-干扰素基因刺激物 (STING) 途径的 I 型干扰素反应。我们表明 TNF 抑制 PINK1 介导的线粒体自噬，导致线粒体功能改变和细胞溶质 mtDNA 水平增加。使用 cGAS-染色质免疫沉淀 (ChIP)，我们证明 TNF 处理后细胞溶质 mtDNA 与 cGAS 结合。此外，TNF 诱导类似于类风湿关节炎患者巨噬细胞的 cGAS-STING 依赖性转录反应。最后，在炎症性关节炎小鼠模型中，cGAS 缺乏阻断了干扰素反应，减少了炎症细胞浸润和关节肿胀。这些发现阐明了将 TNF 与 I 型干扰素信号联系起来的分子机制，并表明在 TNF 驱动的疾病中靶向 cGAS/STING 具有潜在的治疗益处。
