Abstract
The central nervous system (CNS) contains several types of immune cells located in specific anatomic compartments. Macrophages reside at the CNS borders surrounding the brain vessels, in leptomeningeal spaces and the choroid plexus, where they interact with the vasculature and play immunological surveillance and scavenging functions. We investigated the phenotypic changes and role of these macrophages in response to acute ischemic stroke. Given that CD163 expression is a hallmark of perivascular and meningeal macrophages in the rat and human brain, we isolated CD163+ brain macrophages by fluorescence activated cell sorting. We obtained CD163+ cells from control rats and 16 h following transient middle cerebral artery occlusion, after verifying that infiltration of CD163+ peripheral myeloid cells is negligible at this acute time point. Transcriptome analysis of the sorted CD163+ cells identified ischemia-induced upregulation of the hypoxia inducible factor-1 pathway and induction of genes encoding for extracellular matrix components and leukocyte chemoattractants, amongst others. Using a cell depletion strategy, we found that CNS border-associated macrophages participate in granulocyte recruitment, promote the expression of vascular endothelial growth factor (VEGF), increase the permeability of pial and cortical blood vessels, and contribute to neurological dysfunction in the acute phase of ischemia/reperfusion. We detected VEGF expression surrounding blood vessels and in some CD163+ perivascular macrophages in the brain tissue of ischemic stroke patients deceased one day after stroke onset. These findings show ischemia-induced reprogramming of the gene expression profile of CD163+ macrophages that has a rapid impact on leukocyte chemotaxis and blood-brain barrier integrity, and promotes neurological impairment in the acute phase of stroke.
Highlights
The central nervous system (CNS) contains different subsets of myeloid cells under steady-state conditions
Features of CD163+ cells in the control brain and in the acute phase of stroke The CD163+ rat brain cells studied in this work include perivascular macrophages and subpial macrophages that remained attached to the glial limitans after removing the brain from the skull (Fig. 1a)
Flow cytometry of control brain tissue showed a higher level of CD45 expression in CD163+ macrophages than in microglia (CD45lowCD11b+ cells) (Fig. 1b)
Summary
The central nervous system (CNS) contains different subsets of myeloid cells under steady-state conditions. Perivascular macrophages are protective during bacterial meningitis [44], and participate in the clearance of vascular Amyloid-β (Aβ) deposition in mouse models of Alzheimer’s disease [23, 36, 54]. These cells mediate oxidative stress and cerebrovascular dysfunction induced by Aβ [39]. A recent study in the mouse using high-dimensional single-cell cytometry and fate mapping identified different subsets of BAMs and showed differential responses of BAMs compared to other brain myeloid cell populations during aging, experimental autoimmune encephalomyelitis, and in a model of Alzheimer’s disease [37]
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