Siling Du, Feiya Ou, Antoine Drieu, Eric Z. Xu, Yumeng Cheng, Steffen E. Storck, Tornike Mamuladze, Jay Cao, Nora Abduljawad, Bishan Bhattarai, Justin Rustenhoven, Niall Mortimer, Simone Brioschi, Khai M. Nguyen, Patrick Fernandes Rodrigues, Igor Smirnov, Daniel Gibson, J. Michael White, Wandy L. Beatty, David G. DeNardo, Qingyun Li, Michael P. Meers, Claudia Z. Han, Na Sun, Florent Ginhoux, Marina Cella, Marco Colonna, Jonathan Kipnis
Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by interleukin (IL)-34 and C-C chemokine receptor 2 (CCR2). Furthermore, parabiosis and skull-flap transplantation reveal that both blood and skull marrow supply the niche, yielding origin-biased MDM states. Functionally, MDM engraftment enhances cuprizone-mediated demyelination. Together, our study defines the origins, molecular features, and context-dependent roles of brain parenchymal macrophages across homeostasis, turnover, and central nervous system (CNS) pathology.