%0 Journal Article
%A Feng, Ruoqing
%A Spieth, Lena
%A Liu, Lu
%A Berghoff, Stefan
%A Franz, Jonas
%A Liu, Qian
%A Wang, Zhen
%A Tiwari, Vini
%A Vitale, Simona
%A Frerich, Simon
%A Florensa, Sergi
%A Junker, Niklas
%A Huber, Ludwig
%A Keller, Marco
%A Müller, Christoph
%A Bracher, Franz
%A Ge, Xiaoke
%A Rensen, Patrick C N
%A Kooij, Gijs
%A Hosang, Leon
%A Chornyi, Serhii
%A Dichgans, Martin
%A Gokce, Ozgun
%A Saher, Gesine
%A Stadelmann, Christine
%A Giera, Martin
%A Groh, Janos
%A Simons, Mikael
%T Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.
%J Immunity
%V 58
%N 12
%@ 1074-7613
%C [Cambridge, Mass.]
%I Cell Press
%M DZNE-2025-01360
%P 2989 - 3005.e10
%D 2025
%X 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.
%K Animals
%K Multiple Sclerosis: immunology
%K Multiple Sclerosis: genetics
%K Multiple Sclerosis: pathology
%K Multiple Sclerosis: metabolism
%K Mice
%K Encephalomyelitis, Autoimmune, Experimental: immunology
%K Encephalomyelitis, Autoimmune, Experimental: genetics
%K Encephalomyelitis, Autoimmune, Experimental: pathology
%K Microglia: immunology
%K Microglia: metabolism
%K Single-Cell Analysis: methods
%K Transcriptome
%K Inflammation: immunology
%K Inflammation: genetics
%K Gene Expression Profiling
%K Mice, Inbred C57BL
%K Humans
%K CD8-Positive T-Lymphocytes: immunology
%K Female
%K ATP Binding Cassette Transporter 1: genetics
%K ATP Binding Cassette Transporter 1: metabolism
%K Lipid Metabolism
%K Chronic Disease
%K CD8+ T cells (Other)
%K CD8+ tissue-resident memory T cells (Other)
%K glia (Other)
%K lipids (Other)
%K microglia (Other)
%K multiple sclerosis (Other)
%K myelin (Other)
%K neuroinflammation (Other)
%K spatial transcriptomics (Other)
%K ATP Binding Cassette Transporter 1 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41167189
%R 10.1016/j.immuni.2025.10.003
%U https://pub.dzne.de/record/282602