Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation

Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells. Here, we examined the fate of microglia, BAMs, and recruited macrophages upon neuroinflammation and through resolution. Upon infection, Trypanosoma brucei parasites invaded the brain via its border regions, triggering brain barrier disruption and monocyte infiltration. Fate mapping combined with single-cell sequencing revealed microglia accumulation around the ventricles and expansion of epiplexus cells. Depletion experiments using genetic targeting revealed that resident macrophages promoted initial parasite defense and subsequently facilitated monocyte infiltration across brain barriers. These recruited monocyte-derived macrophages outnumbered resident macrophages and exhibited more transcriptional plasticity, adopting antimicrobial gene expression profiles. Recruited macrophages were rapidly removed upon disease resolution, leaving no engrafted monocyte-derived cells in the parenchyma, while resident macrophages progressively reverted toward a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Thus, brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and resolution. [Display omitted] •T. brucei parasites invade the brain via its borders and evoke macrophage expansion•Brain-resident and blood-recruited macrophages show divergent responses•Upon disease resolution, recruited macrophages rapidly disappear and do not engraft•While disease-associated microglia revert toward homeostasis, BAMs remain altered De Vlaminck et al. examine the fate of microglia, border-associated macrophages, and recruited macrophages upon Trypanosoma brucei infection and resolution of neuroinflammation. They show how different types of brain macrophages orchestrate the immune response to invading parasites, revealing that brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and the return to homeostasis.