Authors
Feng R, Spieth L, Liu L, Berghoff S, Franz J, Liu Q, Wang Z, Tiwari V, Vitale S, Frerich S, Florensa S, Junker N, Huber L, Keller M, Müller C, Bracher F, Ge X, Rensen PCN, Kooij G, Hosang L, Chornyi S, Dichgans M, Gokce O, Saher G, Stadelmann C, Giera M, Groh J, Simons M
Journal
Immunity
Citation
Immunity. 2025 Oct 29:S1074-7613(25)00433-9.
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.
