Journal Article

DZNE-2026-00452

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.

Fliegauf, M. ; Levard, D. ; Cardamone, F. ; Frosch, M. ; Kuhn, S. ; Sankowski, R. ; Provinciali, M. ; Dumas, A. A. ; Dalmau Gasull, A. ; Aktories, P. ; Oschwald, A. ; Schwabenland, M. ; Scholz, R.DZNE* ; Beyer, M. D.DZNE* ; Neher, J. J.DZNE* ; Kollefrath, M. ; Baltas, D. ; Reichardt, W. ; von Elverfeldt, D. ; Vivien, D. ; Cupovic, J. ; Iovino, N. ; Rubio, M. ; Amann, L. ; Prinz, M.

2026
Springer Nature Limited London

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Please use a persistent id in citations: doi:10.1038/s41590-026-02457-y

Abstract: Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2+Ly6C+ monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.

Keyword(s): Animals (MeSH) ; Macrophages: immunology (MeSH) ; Macrophages: metabolism (MeSH) ; Macrophages: cytology (MeSH) ; Mice (MeSH) ; Microglia: immunology (MeSH) ; Microglia: metabolism (MeSH) ; Central Nervous System: immunology (MeSH) ; Central Nervous System: cytology (MeSH) ; Monocytes: immunology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Receptors, CCR2: metabolism (MeSH) ; Cell Lineage (MeSH) ; Mice, Transgenic (MeSH) ; Receptors, CCR2

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Contributing Institute(s):

1. Immunogenomics and Neurodegeneration (AG Beyer)
2. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))
3. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

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

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2026

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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 >= 30 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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