Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Department of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
JCI Insight. 2022 Sep 8;7(17):e155250. doi: 10.1172/jci.insight.155250.
STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI) in humans, a disease characterized by spontaneous lung inflammation and fibrosis. Mice with STING gain-of-function mutations (SAVI mice) develop αβ T cell-dependent lung disease and also lack lymph nodes. Although SAVI has been regarded as a type I interferonopathy, the relative contributions of the three interferon receptors are incompletely understood. Here, we show that STING gain of function led to upregulation of IFN-γ-induced chemokines in the lungs of SAVI mice and that deletion of the type II IFN receptor (IFNGR1), but not the type I IFN receptor (IFNAR1) or type III IFN receptor (IFNλR1), ameliorated lung disease and restored lymph node development in SAVI mice. Furthermore, deletion of IFNGR1, but not IFNAR1 or IFNλR1, corrected the ratio of effector to Tregs in SAVI mice and in mixed bone marrow chimeric mice. Finally, cultured SAVI mouse macrophages were hyperresponsive to IFN-γ, but not IFN-β, in terms of Cxcl9 upregulation and cell activation. These results demonstrate that IFNGR1 plays a major role in autoinflammation and immune dysregulation mediated by STING gain of function.
STING 功能获得性突变导致人类 STING 相关性血管病伴婴儿期起病（SAVI），这是一种以自发性肺部炎症和纤维化为特征的疾病。具有 STING 功能获得性突变的小鼠（SAVI 小鼠）会发展出依赖于 αβ T 细胞的肺部疾病，并且还缺乏淋巴结。尽管 SAVI 被认为是一种 I 型干扰素病，但三种干扰素受体的相对贡献尚不完全清楚。在这里，我们表明 STING 功能获得导致 SAVI 小鼠肺部 IFN-γ诱导趋化因子的上调，并且缺失 II 型干扰素受体（IFNGR1），而不是 I 型干扰素受体（IFNAR1）或 III 型干扰素受体（IFNλR1），可改善肺部疾病并恢复 SAVI 小鼠的淋巴结发育。此外，缺失 IFNGR1，但不是 IFNAR1 或 IFNλR1，可纠正 SAVI 小鼠和混合骨髓嵌合小鼠中效应细胞与 Treg 细胞的比例。最后，培养的 SAVI 小鼠巨噬细胞对 IFN-γ的反应过度，而对 IFN-β的反应则不然，表现在 Cxcl9 的上调和细胞激活方面。这些结果表明 IFNGR1 在 STING 功能获得介导的自身炎症和免疫失调中起主要作用。
