Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)–stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi–Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1 –/– background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1 –/– mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.

中文翻译：

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经典树突状细胞中的 cGAS 激活导致 TREX1 缺陷小鼠的自身免疫


通过环状 GMP-AMP （cGAMP） 合酶 （cGAS） 干扰素基因刺激剂 （STING） 途径检测胞质 DNA，可提供针对病原体和癌症的免疫防御，但过度激活时也可引起自身免疫。核酸外切酶三重修复核酸外切酶 1 （TREX1） 降解胞质溶胶中的 DNA，并阻止自身 DNA 激活 cGAS。TREX1 基因的功能丧失突变与 Aicardi-Goutières 综合征等自身免疫性疾病有关，缺乏 TREX1 的小鼠以 cGAS 依赖性方式发展为致命性炎症。为了确定 cGAS 激活驱动自身炎症的细胞类型，我们在 Trex1 –/– 背景上生成了条件性 cGAS 敲除小鼠。在这里，我们表明经典树突状细胞 （cDC） 中 cGAS 基因的遗传消融，而不是在巨噬细胞中，足以将 Trex1 –/– 小鼠从所有观察到的疾病表型中拯救出来，包括致死性、T 细胞活化、组织炎症以及抗核抗体和干扰素刺激基因的产生。这些结果表明，cDC 中的 cGAS 激活响应在没有 TREX1 的情况下积累的自身 DNA 而引起自身炎症。