| First Author | Stinson WA | Year | 2022 |
| Journal | JCI Insight | Volume | 7 |
| Issue | 17 | PubMed ID | 36073546 |
| Mgi Jnum | J:334207 | Mgi Id | MGI:7344915 |
| Doi | 10.1172/jci.insight.155250 | Citation | Stinson WA, et al. (2022) The IFN-gamma receptor promotes immune dysregulation and disease in STING gain-of-function mice. JCI Insight 7(17):e155250 |
| abstractText | 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 alphabeta 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-gamma-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 (IFNlambdaR1), ameliorated lung disease and restored lymph node development in SAVI mice. Furthermore, deletion of IFNGR1, but not IFNAR1 or IFNlambdaR1, 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-gamma, but not IFN-beta, 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. |
