Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.

18/03/2026

Nature immunology

Authors: Maximilian Fliegauf, Damien Levard, Francesco Cardamone, Maximilian Frosch, Siegmar Kuhn, Roman Sankowski, Martino Provinciali, Anaelle Aurelie Dumas, Adrià Dalmau Gasull, Philipp Aktories, Alexander Oschwald, Marius Schwabenland, Rebekka Scholz, Marc D Beyer, Jonas J Neher, Michael Kollefrath, Dimos Baltas, Wilfried Reichardt, Dominik von Elverfeldt, Denis Vivien, Jovana Cupovic, Nicola Iovino, Marina Rubio, Lukas Amann, Marco Prinz

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 CCR2Ly6C 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.

PMID: 41851525