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
{"title":"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。","authors":"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","doi":"10.1016/j.immuni.2024.05.017","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5000,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250091/pdf/","citationCount":"0","resultStr":"{\"title\":\"The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.\",\"authors\":\"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\",\"doi\":\"10.1016/j.immuni.2024.05.017\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":13269,\"journal\":{\"name\":\"Immunity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":25.5000,\"publicationDate\":\"2024-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250091/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.immuni.2024.05.017\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/14 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2024.05.017","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/14 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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.
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.