Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions
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<sup>+</sup> 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
- Xiaoke Ge (ORCID: https://orcid.org/0000-0003-0815-1076)
- Niels Junker (ORCID: https://orcid.org/0000-0001-8348-9363)
- Janos Groh (ORCID: https://orcid.org/0000-0002-7628-0163)
- Serhii Chornyi (ORCID: https://orcid.org/0000-0003-4817-1127)
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Christoph Müller (ORCID: https://orcid.org/0000-0002-1163-2527)
- Marco Keller (ORCID: https://orcid.org/0000-0003-4792-3980)
- Susan Vitale (ORCID: https://orcid.org/0000-0002-5972-6848)
- Patrick C.N. Rensen (ORCID: https://orcid.org/0000-0002-8455-4988)
- Christine Stadelmann (ORCID: https://orcid.org/0000-0003-1766-5458)
- Franz Bracher (ORCID: https://orcid.org/0000-0003-0009-8629)
- Lena Spieth (ORCID: https://orcid.org/0000-0002-0308-0144)
- Martin Dichgans (ORCID: https://orcid.org/0000-0002-0654-387X)
- Stefan A. Berghoff (ORCID: https://orcid.org/0000-0002-3794-7295)
- Leon Hosang
- Gijs Kooij (ORCID: https://orcid.org/0000-0002-9488-2918)
- Gesine Saher (ORCID: https://orcid.org/0000-0003-3507-9604)
- Simon Frerich (ORCID: https://orcid.org/0000-0002-8275-6113)
- Vini Tiwari (ORCID: https://orcid.org/0000-0001-6455-3999)
- Mikael Simons (ORCID: https://orcid.org/0000-0001-5329-192X)
- Ludwig Huber (ORCID: https://orcid.org/0000-0002-0217-136X)
- Jonas Franz (ORCID: https://orcid.org/0000-0001-7523-6622)
- Özgün Gökçe (ORCID: https://orcid.org/0000-0001-6319-404X)
- Lu Liu (ORCID: https://orcid.org/0000-0002-6233-0705)
- Ruoqing Feng
- Qian Liu (ORCID: https://orcid.org/0000-0002-5952-1164)
- Sergi Florensa
Institutions
- Leiden University Medical Center (NL)
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- Netherlands Metabolomics Centre (NL)
- Amsterdam Neuroscience (NL)
- Munich Cluster for Systems Neurology (DE)
- Universitätsmedizin Göttingen (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Immunity
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1016/j.immuni.2025.10.003
- Citations
- 6
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 4.84