Journal Article

DZNE-2025-00681

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.

Groh, J. (First author)DZNE* ; Feng, R.DZNE* ; Yuan, X.DZNE* ; Liu, L.DZNE* ; Klein, D. ; Hutahaean, G. ; Butz, E.DZNE* ; Wang, Z.DZNE* ; Steinbrecher, L.DZNE* ; Neher, J.DZNE* ; Martini, R. ; Simons, M. (Last author)DZNE*

2025
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/s41593-025-01955-w

Abstract: Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.

Keyword(s): Animals (MeSH) ; Microglia: immunology (MeSH) ; Microglia: metabolism (MeSH) ; White Matter: pathology (MeSH) ; White Matter: immunology (MeSH) ; White Matter: metabolism (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; CD8-Positive T-Lymphocytes: metabolism (MeSH) ; Mice (MeSH) ; Aging: pathology (MeSH) ; Aging: immunology (MeSH) ; Chemokine CXCL10: metabolism (MeSH) ; Chemokine CXCL10: immunology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Receptors, CXCR3: metabolism (MeSH) ; Myelin Sheath (MeSH) ; Male (MeSH) ; Mice, Transgenic (MeSH) ; Nerve Degeneration: pathology (MeSH) ; Nerve Degeneration: immunology (MeSH) ; Chemokine CXCL10 ; Receptors, CXCR3 ; Cxcl10 protein, mouse ; Cxcr3 protein, mouse

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)
2. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))
3. Neuroimmunology and Neurodegenerative Disease (AG Neher (Tübingen))

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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