Patients with stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI) develop systemic inflammation characterized by vasculopathy, interstitial lung disease, ulcerative skin lesions, and premature death. Autosomal dominant mutations in STING are thought to trigger activation of IRF3 and subsequent up-regulation of interferon (IFN)-stimulated genes (ISGs) in patients with SAVI. We generated heterozygous STING N153S knock-in mice as a model of SAVI. These mice spontaneously developed inflammation within the lung, hypercytokinemia, T cell cytopenia, skin ulcerations, and premature death. Cytometry by time-of-flight (CyTOF) analysis revealed that the STING N153S mutation caused myeloid cell expansion, T cell cytopenia, and dysregulation of immune cell signaling. Unexpectedly, we observed only mild up-regulation of ISGs in STING N153S fibroblasts and splenocytes and STING N154S SAVI patient fibroblasts. STING N153S mice lacking IRF3 also developed lung disease, myeloid cell expansion, and T cell cytopenia. Thus, the SAVI-associated STING N153S mutation triggers IRF3-independent immune cell dysregulation and lung disease in mice.

患有干扰素基因刺激物（STING）的婴幼儿发作性血管病（SAVI）的患者会出现以血管病，间质性肺病，溃疡性皮肤病变和过早死亡为特征的全身性炎症。人们认为STING中的常染色体显性突变会触发IRF3的激活以及随后SAVI患者干扰素（IFN）刺激基因（ISG）的上调。我们生成了杂合的STING N153S敲入小鼠作为SAVI的模型。这些小鼠自发发展为肺内炎症，高细胞血症，T细胞血细胞减少，皮肤溃疡和过早死亡。飞行时间流式细胞术（CyTOF）分析显示，STING N153S突变引起骨髓细胞扩张，T细胞血细胞减少和免疫细胞信号传导异常。不料，我们仅观察到STING N153S成纤维细胞和脾细胞以及STING N154S SAVI患者成纤维细胞中ISG的轻度上调。缺少IRF3的STING N153S小鼠也患有肺部疾病，骨髓细胞扩增和T细胞血细胞减少症。因此，与SAVI相关的STING N153S突变触发了小鼠中独立于IRF3的免疫细胞失调和肺部疾病。