澳大利亚悉尼大学Markus J. Hofer和英国爱丁堡大学David P.J. Hunt共同合作，近期取得重要工作进展。他们研究提出，脑微血管是人类脑干扰素病中干扰素-α神经毒性的主要介质。相关研究成果2024年6月14日在线发表于《免疫》杂志上。

据介绍，Aicardi-Goutières综合征（AGS）是一种以干扰素（IFN）-α产生异常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的主要来源和靶点尚不清楚。

研究人员证明了大脑是AGS中神经毒性IFN-α的主要来源，并使用星形胶质细胞驱动的小鼠Ifna1错误表达证实了脑内IFN-α具有神经毒性。使用单细胞RNA测序，研究人员证明了大脑内皮细胞内的脑内IFN-α激活受体（IFNAR）信号传导，导致了一种独特的大脑小血管疾病，与AGS患者相似。

磁共振成像（MRI）和单分子ELISA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。小鼠内皮细胞Ifnar1的消融挽救了微血管疾病，阻止了弥漫性脑疾病的发展，并延长了寿命。

总之，这一研究结果表明，脑微血管是AGS中IFN-α神经毒性的主要介质，是治疗干预的可接近靶点。

附：英文原文

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

Author: 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

Issue&Volume: 2024-06-14

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.

DOI: 10.1016/j.immuni.2024.05.017

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00271-1