Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions
Immunity, vol. 58, pp. 2989–3005.e10
Abstract
Compartmentalized inflammation is a key driver of multiple sclerosis (MS) progression, but the mechanisms sustaining its persistence remain unclear. A hallmark of this persistent and slowly evolving inflammatory process is chronic active MS lesions. We generated a high-resolution, single-cell molecular and spatial atlas of such lesions by combining single-nucleus RNA sequencing (snRNA-seq) with multiplexed error-robust fluorescence in situ hybridization (MERFISH). Within lesion rims, we identified CD8 + T cell niches associated with inflamed microglia displaying an interferon response and upregulated lipid metabolism. To investigate their function, we deleted ATP-binding cassette transporters A1 and G1 (ABCA1/G1) in the microglia of mice with experimental autoimmune encephalomyelitis (EAE), which increased the formation of lipid-storing phagocytes that amplified inflammation. Moreover, pharmacologically targeting sterol metabolism mitigated foam cell formation and inflammatory demyelination in EAE. Thus, our high-resolution map of immune niches in chronic active MS lesions identifies a role for lipid-storing, dysfunctional microglia in persistent neuroinflammation.
Authors 23
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German Center for Neurodegenerative Diseases · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany
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German Center for Neurodegenerative Diseases · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany
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German Center for Neurodegenerative Diseases · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany
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Stefan A. Berghoff corresponding
German Center for Neurodegenerative Diseases · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany. Electronic address: stefan.berghoff@dzne.de
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Affiliation as printed
Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
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German Center for Neurodegenerative Diseases · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany
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Institut für Schlaganfall- und Demenzforschung · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany
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German Center for Neurodegenerative Diseases · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany
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Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Pharmacy, Center for Drug Research, LMU Munich, Munich, Germany
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Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Pharmacy, Center for Drug Research, LMU Munich, Munich, Germany
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Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Pharmacy, Center for Drug Research, LMU Munich, Munich, Germany
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Xiaoke Ge Aachen Division of Endocrinology Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Endocrinology, Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Patrick C.N. Rensen Aachen Division of Endocrinology Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Endocrinology, Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, the Netherlands
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Affiliation as printed
Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany
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Serhii Chornyi Aachen
Leiden University Medical Center · Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, the Netherlands
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LMU Klinikum · Munich Cluster for Systems Neurology · Institut für Schlaganfall- und Demenzforschung · Ludwig-Maximilians-Universität München
Affiliation as printed
German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster of Systems Neurology, Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany
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University Hospital Bonn · German Center for Neurodegenerative Diseases
Affiliation as printed
German Center for Neurodegenerative Diseases, Bonn, Germany; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
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Max Planck Institute for Multidisciplinary Sciences
Affiliation as printed
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
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Affiliation as printed
Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
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Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
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Janos Groh corresponding
German Center for Neurodegenerative Diseases · Munich Cluster for Systems Neurology · Technical University of Munich
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster of Systems Neurology, Munich, Germany. Electronic address: janos.groh@tum.de
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Mikael Simons corresponding
Munich Cluster for Systems Neurology · Institut für Schlaganfall- und Demenzforschung · Technical University of Munich · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster of Systems Neurology, Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany. Electronic address: mikael.simons@dzne.de
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