The brain-meningeal interface functions as a reservoir and entry site for brain parenchymal macrophages

Microglia are regarded as self-maintaining brain parenchymal macrophages without contribution from adult hematopoiesis. While peripheral macrophage engraftment into the brain has been reported, the biological variables governing central nervous system (CNS) macrophage niche access remain unclear. We show that CNS macrophage engraftment depends on (1) the balance between tissue-resident macrophage (TRM) self-renewal, (2) the temporal alignment of niche opening with the availability of engraftment-competent cells and (3) proximity to the vacated niche, rather than prolonged niche vacancy. Fate mapping revealed that monocytes entering the subdural space undergo border-associated macrophage (BAM)-like differentiation, clonal expansion, and transpial migration into the parenchyma, whereas mature BAMs directly repopulate selectively vacated parenchymal niches. We further identified a parenchymal macrophage population with a peripheral BAM-like transcriptional program in aged and neurodegenerative human brains, challenging the dogma of MG-exclusivity. Together, these discoveries provide a predictive framework for understanding macrophage maintenance and replacement, and for developing macrophage-based cellular therapies.