| First Author | Viengkhou B | Year | 2024 |
| Journal | Immunity | Volume | 57 |
| Issue | 7 | Pages | 1696-1709.e10 |
| PubMed ID | 38878770 | Mgi Jnum | J:360197 |
| Mgi Id | MGI:7665166 | Doi | 10.1016/j.immuni.2024.05.017 |
| Citation | Viengkhou B, et al. (2024) The brain microvasculature is a primary mediator of interferon-alpha neurotoxicity in human cerebral interferonopathies. Immunity 57(7):1696-1709.e10 |
| abstractText | Aicardi-Goutieres syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-alpha production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-alpha remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-alpha in AGS and confirmed the neurotoxicity of intracerebral IFN-alpha using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-alpha-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-alpha was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-alpha neurotoxicity in AGS, representing an accessible target for therapeutic intervention. |
