GSE212078
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 with important homeostatic functions. However, their fate during and after severe episodes of brain inflammation and their relation to recruited monocyte-derived cells remain poorly understood. Here, we show that Trypanosoma brucei parasites invade the brain via its border regions, triggering a disruption of brain barriers and the recruitment of large numbers of monocytes. Fate-mapping combined with single-cell sequencing revealed the remarkable dynamics of resident macrophages, including microglia accumulation around the ventricular ependyma and an expansion of epiplexus cells. Resident macrophages were important for attracting peripheral immune cells and driving a pro-inflammatory response. However, recruited monocyte-derived macrophages reached higher cell densities and exhibited more transcriptional plasticity, adopting anti-microbial gene expression profiles not observed resident macrophages. Remarkably, recruited macrophages were short-lived and rapidly removed upon disease resolution, while activated resident macrophages progressively reverted towards a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Together our results reveal the diverging responses and dynamics of resident and recruited macrophages upon Trypanosome invasion of the brain. Overall design: Myeloid cells were isolated from whole brain samples and brain border tissues of naive mice, T. b. brucei infected mice, and mice cured from infection. Cells were sorted by FACS (Fluorescence-activated cell sorting) through detection of CD45 and/or CD11b and CX3CR1 expression, and subsequently analyzed using scRNA-seq. Whole brain samples of naive and infected mice used n=4 mice/group. Whole brain samples of mice cured from late-stage infection (n=2-3 mice/group) was compared to that of late-stage infected mice (or cured day 0; 3 mice/group). Choroid plexus border tissue of infected mice (n=8 mice) was compared to previously published data in naive mice (Van Hove et al. 2019). And border tissues of cured mice (n=8 mice) were compared to non-infected age-matched littermate controls (n=6 mice).