TY  - JOUR
AU  - Feng, Ruoqing
AU  - Spieth, Lena
AU  - Liu, Lu
AU  - Berghoff, Stefan
AU  - Franz, Jonas
AU  - Liu, Qian
AU  - Wang, Zhen
AU  - Tiwari, Vini
AU  - Vitale, Simona
AU  - Frerich, Simon
AU  - Florensa, Sergi
AU  - Junker, Niklas
AU  - Huber, Ludwig
AU  - Keller, Marco
AU  - Müller, Christoph
AU  - Bracher, Franz
AU  - Ge, Xiaoke
AU  - Rensen, Patrick C N
AU  - Kooij, Gijs
AU  - Hosang, Leon
AU  - Chornyi, Serhii
AU  - Dichgans, Martin
AU  - Gokce, Ozgun
AU  - Saher, Gesine
AU  - Stadelmann, Christine
AU  - Giera, Martin
AU  - Groh, Janos
AU  - Simons, Mikael
TI  - Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.
JO  - Immunity
VL  - 58
IS  - 12
SN  - 1074-7613
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-01360
SP  - 2989 - 3005.e10
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Multiple Sclerosis: immunology
KW  - Multiple Sclerosis: genetics
KW  - Multiple Sclerosis: pathology
KW  - Multiple Sclerosis: metabolism
KW  - Mice
KW  - Encephalomyelitis, Autoimmune, Experimental: immunology
KW  - Encephalomyelitis, Autoimmune, Experimental: genetics
KW  - Encephalomyelitis, Autoimmune, Experimental: pathology
KW  - Microglia: immunology
KW  - Microglia: metabolism
KW  - Single-Cell Analysis: methods
KW  - Transcriptome
KW  - Inflammation: immunology
KW  - Inflammation: genetics
KW  - Gene Expression Profiling
KW  - Mice, Inbred C57BL
KW  - Humans
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - Female
KW  - ATP Binding Cassette Transporter 1: genetics
KW  - ATP Binding Cassette Transporter 1: metabolism
KW  - Lipid Metabolism
KW  - Chronic Disease
KW  - CD8+ T cells (Other)
KW  - CD8+ tissue-resident memory T cells (Other)
KW  - glia (Other)
KW  - lipids (Other)
KW  - microglia (Other)
KW  - multiple sclerosis (Other)
KW  - myelin (Other)
KW  - neuroinflammation (Other)
KW  - spatial transcriptomics (Other)
KW  - ATP Binding Cassette Transporter 1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41167189
DO  - DOI:10.1016/j.immuni.2025.10.003
UR  - https://pub.dzne.de/record/282602
ER  -