在人类大脑干扰素病中,脑微血管是干扰素-α神经毒性的主要介质。

IF 25.5 1区 医学 Q1 IMMUNOLOGY Immunity Pub Date : 2024-07-09 Epub Date: 2024-06-14 DOI:10.1016/j.immuni.2024.05.017
Barney Viengkhou, Emina Hayashida, Sarah McGlasson, Katie Emelianova, Deborah Forbes, Stewart Wiseman, Joanna Wardlaw, Rovin Verdillo, Sarosh R Irani, Darragh Duffy, Fredrik Piehl, Lipin Loo, Axel Pagenstecher, G Greg Neely, Yanick J Crow, Iain L Campbell, David P J Hunt, Markus J Hofer
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引用次数: 0

摘要

艾卡迪-古铁雷斯综合征(AGS)是一种以干扰素(IFN)-α异常分泌为特征的自身炎症性疾病。AGS发病的主要原因是脑部疾病,但神经毒性IFN-α的主要来源和靶点仍不清楚。在这里,我们证明了大脑是 AGS 中神经毒性 IFN-α 的主要来源,并利用星形胶质细胞驱动的 Ifna1 在小鼠体内的误表达证实了脑内 IFN-α 的神经毒性。通过单细胞 RNA 测序,我们证明了脑内皮细胞中的 IFN-α 激活受体(IFNAR)信号传导会导致一种独特的脑小血管疾病,这种疾病与在 AGS 患者中观察到的类似。磁共振成像(MRI)和单分子酶联免疫吸附试验显示,中枢而非外周 IFN-α 是人类微血管疾病的主要决定因素。对小鼠内皮细胞 Ifnar1 的消融可挽救微血管疾病,阻止弥漫性脑疾病的发展,并延长寿命。这些结果确定了脑微血管是IFN-α对AGS神经毒性的主要介质,是治疗干预的可及靶点。
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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.

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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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