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

ABSTRACT: 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.

SUBMITTER: Viengkhou B

PROVIDER: S-EPMC11250091 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Viengkhou Barney B Hayashida Emina E McGlasson Sarah S Emelianova Katie K Forbes Deborah D Wiseman Stewart S Wardlaw Joanna J Verdillo Rovin R Irani Sarosh R SR Duffy Darragh D Piehl Fredrik F Loo Lipin L Pagenstecher Axel A Neely G Greg GG Crow Yanick J YJ Campbell Iain L IL Hunt David P J DPJ Hofer Markus J MJ

Immunity 20240614 7

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 intrac ...[more]

PMID: 38878770

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Project description:BackgroundJuvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI.MethodsA peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics.ResultsIRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients' IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (rs = 0.33-0.47) and more strongly with skin activity (rs = 0.58-0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S.ConclusionsOur findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.

Dataset Information

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

Publications

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

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