STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disorder characterized by blood vessel occlusions, acral necrosis, myositis, rashes, and pulmonary inflammation that are the result of activating mutations in the STimulator of Interferon Genes (STING). We generated a transgenic line that recapitulates many of the phenotypic aspects of SAVI by targeting the expression of the human STING-N154S-mutant protein to the murine hematopoietic compartment. hSTING-N154S mice demonstrated failure to gain weight, lymphopenia, progressive paw swelling accompanied by inflammatory infiltrates, severe myositis, and ear and tail necrosis. However, no significant lung inflammation was observed. X-ray microscopy imaging revealed vasculopathy characterized by arteriole occlusions and venous thromboses. Type I interferons and proinflammatory mediators were elevated in hSTING-N154S sera. Importantly, the phenotype was prevented in hSTING-N154S mice lacking the type I interferon receptor gene (Ifnar1). This model, based on a mutant human STING protein, may shed light on the pathophysiological mechanisms operative in SAVI.

中文翻译：

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组成性活性人STING突变体在造血细胞中的表达在小鼠中产生了Ifnar1依赖性血管病。

婴儿期起病（SAVI）的STING相关血管病是一种自身炎症性疾病，其特征是血管阻塞，急性坏死，肌炎，皮疹和肺部炎症，这是干扰素基因刺激因子（STING）激活突变的结果。我们通过将人STING-N154S突变蛋白的表达靶向鼠造血区室，产生了一个概括SAVI许多表型特征的转基因系。hSTING-N154S小鼠表现出体重增加失败，淋巴细胞减少，爪进行性肿胀并伴有炎性浸润，严重的肌炎以及耳尾坏死。但是，未观察到明显的肺部炎症。X射线显微镜成像显示以小动脉闭塞和静脉血栓形成为特征的血管病变。hSTING-N154S血清中I型干扰素和促炎介质增加。重要的是，在缺乏I型干扰素受体基因（Ifnar1）的hSTING-N154S小鼠中，该表型得到了预防。该模型基于突变的人STING蛋白，可以阐明在SAVI中起作用的病理生理机制。