The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)- production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN- remains unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN- in AGS, and confirmed neurotoxicity of intracerebral IFN- using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN- activated IFNAR signaling within cerebral endothelial cells, caused a distinctive cerebral small vessel disease similarly observed in individuals with AGS. MRI and single-molecule ELISA revealed that central and not peripheral IFN- was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped development of diffuse brain disease and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN- neurotoxicity in AGS, representing an accessible target for therapeutic intervention.