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)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-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-α 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-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention. [Display omitted] • Neurotoxic IFN-α in Aicardi-Goutières syndrome (AGS) is primarily of cerebral origin • Endothelial cells are critical cellular targets of neurotoxic IFN-α • Chronically elevated intracerebral IFN-α causes a distinct cerebral microangiopathy • Neurodegeneration arises as a secondary consequence of IFN-α-driven microangiopathy Aicardi-Goutières syndrome is an autoinflammatory brain disease associated with increased interferon-α production, but the primary source and mediators of neurotoxicity are poorly described. Viengkhou et al. show that neurotoxic interferon-α originates in the central nervous system and mediates disease primarily through its effects on the cerebral microvasculature. This represents an accessible target for therapeutic intervention. [ABSTRACT FROM AUTHOR]