Department of Molecular Biology and Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
Proc Natl Acad Sci U S A. 2024 Sep 17;121(38):e2411747121. doi: 10.1073/pnas.2411747121. Epub 2024 Sep 10.
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.
环鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）-干扰素基因刺激物（STING）通路检测细胞质 DNA 可提供针对病原体和癌症的免疫防御，但当过度激活时也会引起自身免疫。三磷酸外切核酸酶 3' 修复外切核酸酶 1（TREX1）在细胞质中降解 DNA，防止自身 DNA 激活 cGAS。TREX1 基因的功能丧失突变与自身免疫性疾病有关，如 Aicardi-Goutières 综合征，缺乏 TREX1 的小鼠以 cGAS 依赖性方式发生致命性炎症。为了确定 cGAS 激活驱动自身炎症的细胞类型，我们在 Trex1 背景下生成了条件性 cGAS 敲除小鼠。在这里，我们表明在经典树突状细胞（cDC）中而不是在巨噬细胞中遗传消融 cGAS 基因足以挽救 Trex1 小鼠的所有观察到的疾病表型，包括致死性、T 细胞激活、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，在 TREX1 缺失的情况下，cDC 中 cGAS 的激活会导致自身免疫反应，从而导致自身 DNA 的积累。
