The IFN-γ receptor promotes immune dysregulation and disease in STING gain-of-function mice
W. Alexander Stinson, Cathrine A. Miner, Fang R. Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J. Miner
W. Alexander Stinson, Cathrine A. Miner, Fang R. Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J. Miner
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Research Article Inflammation

The IFN-γ receptor promotes immune dysregulation and disease in STING gain-of-function mice

Abstract

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.

Authors

W. Alexander Stinson, Cathrine A. Miner, Fang R. Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J. Miner

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Figure 1

The type II IFN receptor promotes lung disease in SAVI mice.

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The type II IFN receptor promotes lung disease in SAVI mice. (A) Represe...
(A) Representative images of H&E-stained lung sections from 13- to 16-week-old STING N153S (SAVI) mice or the corresponding knockout (KO) animals lacking the indicated IFN receptor. Images are representative of n = 9–16 mice per group. The top row of images was taken under low magnification, and bottom row was taken under high magnification. Scale bars: 100 μm. Original magnification, ×4 (top); ×20 (bottom). (B) Quantitation of perivascular inflammation in the lungs from mice of indicated genotypes from A. Data are shown as the mean ± SEM. (C–G) ISG and cytokine expression in lungs from WT and SAVI animals of the indicated IFN receptor genotype. Data are shown as the mean ± SEM from n = 9–15 mice from 3 to 6 independent experiments. (H) Differentially upregulated transcriptional programs following STING activation in naive CD4+ T cells from the publicly available data set GSE100411 (20). Gene sets were obtained from the MSigDB Hallmark collection (45). (I) Enrichment plot of the hallmark IFN-γ response gene set following STING activation in naive CD4+ T cells (20). Fisher’s exact test and normalized enrichment score (NES) are included. Data in B–G were analyzed by Kruskal-Wallis test, comparing lung disease (B) or gene expression (C–G) in the lungs of the indicated knockout animals to values in the SAVI reference group. Statistical significance of differentially expressed gene sets in I was computed by Fisher’s exact test with Benjamini-Hochberg correction (FDR = 5%) using Enrichr (41–43), which reports the adjusted P value as a Q value. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.