Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, 350117, China.
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, 350117, China; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
J Autoimmun. 2019 Jun;100:84-94. doi: 10.1016/j.jaut.2019.03.001. Epub 2019 Mar 11.
TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi-Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1 mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1 mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.
TREX1 编码一种主要的细胞 DNA 核酸外切酶。该基因的突变会导致人体细胞内 DNA 的积累，从而引发自身免疫性疾病，包括 Aicardi-Goutières 综合征（AGS）和系统性红斑狼疮（SLE）。我们通过在 Trex1 基因中设计 D18N 突变来创建狼疮小鼠模型，该突变会使酶失活，并且已经在具有狼疮样疾病的人类患者中发现。Trex1 小鼠表现出全身性炎症，一致地重现了人类 AGS 和 SLE 的许多特征。重要的是，在 Trex1 小鼠中敲除 cGas 基因可挽救致死性和所有可检测到的病理表型，包括多器官炎症、干扰素刺激基因诱导、自身抗体产生和异常 T 细胞激活。这些结果表明 cGAS 是与 TREX1 功能缺陷相关的自身免疫性疾病的关键介质，为疾病发病机制提供了更多的见解，并为治疗人类系统性自身免疫性疾病的药物开发提供了指导。
