Journal Article

DZNE-2025-01360

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.

Feng, R. (First author)DZNE* ; Spieth, L.DZNE* ; Liu, L.DZNE* ; Berghoff, S.DZNE* ; Franz, J. ; Liu, Q.DZNE* ; Wang, Z.DZNE* ; Tiwari, V.DZNE* ; Vitale, S.DZNE* ; Frerich, S. ; Florensa, S.DZNE* ; Junker, N.DZNE* ; Huber, L.DZNE* ; Keller, M. ; Müller, C. ; Bracher, F. ; Ge, X. ; Rensen, P. C. N. ; Kooij, G. ; Hosang, L. ; Chornyi, S. ; Dichgans, M.DZNE* ; Gokce, O.DZNE* ; Saher, G. ; Stadelmann, C. ; Giera, M. ; Groh, J.DZNE* ; Simons, M. (Last author)DZNE*

2025
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.immuni.2025.10.003

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.

Keyword(s): Animals (MeSH) ; Multiple Sclerosis: immunology (MeSH) ; Multiple Sclerosis: genetics (MeSH) ; Multiple Sclerosis: pathology (MeSH) ; Multiple Sclerosis: metabolism (MeSH) ; Mice (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: immunology (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: genetics (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: pathology (MeSH) ; Microglia: immunology (MeSH) ; Microglia: metabolism (MeSH) ; Single-Cell Analysis: methods (MeSH) ; Transcriptome (MeSH) ; Inflammation: immunology (MeSH) ; Inflammation: genetics (MeSH) ; Gene Expression Profiling (MeSH) ; Mice, Inbred C57BL (MeSH) ; Humans (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; Female (MeSH) ; ATP Binding Cassette Transporter 1: genetics (MeSH) ; ATP Binding Cassette Transporter 1: metabolism (MeSH) ; Lipid Metabolism (MeSH) ; Chronic Disease (MeSH) ; CD8+ T cells ; CD8+ tissue-resident memory T cells ; glia ; lipids ; microglia ; multiple sclerosis ; myelin ; neuroinflammation ; spatial transcriptomics ; ATP Binding Cassette Transporter 1

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)
2. Innate Immunity in Neurodegeneration (AG Latz)
3. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
4. Spatial Dynamics of Neurodegeneration (AG Gokce)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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