The fate and dynamics of microglia, border macrophages and infiltrating monocytes during the onset and resolution of infectious neuroinflammation Karen De Vlaminck1,2, Hannah Van Hove1,2, Ana Rita Pombo Antunes1,2, Liesbet Martens3, Sofie De Prijck4, Niels Vandamme3, Benoit Stijlemans1,2, Yvan Saeys3, Martin Guilliams4, Roosmarijn Vandenbroucke5, Jo Van Ginderachter1,2, Kiavash Movahedi1,2* 1Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Belgium; 2Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Belgium; 3Data Mining and Modelling for Biomedicine Group, VIB Inflammation Research Center, Belgium; 4Lab of Immunoregulation, VIB Inflammation Research Center, Belgium; 5Lab of Barriers in Inflammation, VIB Inflammation Research Center, Belgium
Microglia and CNS border macrophages are embryonically-derived phagocytes that can self-maintain in situ. However, during disease conditions monocytes can gain access to the brain, but their fate remains unclear. Here, we show that the unicellular parasite Trypanosoma brucei invaded the brain in a coordinated step-wise fashion, moving from the meninges to the choroid plexus and the surrounding brain parenchyma. This resulted in the disruption of brain barriers, leading to a massive infiltration of monocytes that entered the brain via its borders or via parenchymal hotspots. Using serial 2-photon tomography and fate mapping combined with single-cell RNA sequencing of the brain or its borders, we uncovered the fate and transcriptional dynamics of microglia, border macrophages and infiltrating monocytes, both during the infection and resolution phase. We show that during inflammation, microglia and border macrophages expanded from an internal pool, became highly dynamic and moved into parasite-infected regions, while monocytes strictly differentiated into a heterogeneous population of inflammatory macrophages. Remarkably, within a week following drug-induced parasite clearance, microglia re-adopted a homeostatic transcriptional state. Furthermore, inflammatory macrophages were quickly removed from the brain, leaving no bone marrow input in the microglial pool. Border macrophages did receive bone marrow input during the resolution phase, but the extent was highly dependent upon their anatomical niche. Our results emphasize the astonishing plasticity and resilience of resident brain macrophages and highlight a dichotomy between resident and recruited phagocytes upon brain inflammation.
Credits: None available.
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