Immune surveillance of mouse brain perivascular spaces by blood‐borne macrophages

Abstract

Virchow-Robin's perivascular spaces lie between the basement membrane around pericytes and the basement membrane at the surface of the glia limitans of the brain vessels. They are directly connected to the subpial space and harbour a population of cells distinct from pericytes, perivascular microglia and other cells within perivascular spaces (e.g. T cells and mast cells) in their ability to quickly phagocytose particles from the cerebrospinal fluid (CSF). Morphology, function, and cell surface proteins of these perivascular cells suggest an origin from the monocyte/macrophage lineage. It is currently unclear to what extent these brain perivascular cells represent a resident population of histiocytes or undergo continuous supplementation from blood monocytes. Using transplants of green-fluorescent-protein (GFP)-transfected bone marrow cells, we therefore investigated the replacement of perivascular cells by blood-borne macrophages in adult mice. GFP-positive cells in the perivascular spaces were found as early as 2 weeks post transplantation. The substitution of host perivascular cells by donor-derived macrophages was then evaluated using immunocytochemistry and intraventricular injection of hydrophilic rhodamine-fluorescent tracers. Such tracers diffuse along perivascular spaces and are subsequently phagocytosed by perivascular cells leading to stable phagocytosis-dependent labelling. Thus, the population of newly immigrated macrophages could be related to the total number of perivascular macrophages. This approach revealed a continuous increase of donor-derived perivascular cells. At 14 weeks post transplantation, all perivascular cells were donor-derived. These data show that brain perivascular cells are a population of migratory macrophages and not resident histiocytes.

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

“…After intracranial injection, the hydrophilic fluorescent dextran dyes diffuse along the perivascular space and are absorbed by essentially all perivascular macrophages (>98%) via non-specific micropinocytosis. 25,30,49 To establish a baseline for subsequent perivascular macrophage turnover, all animals (n Z 12) received fluoresceinconjugated dextran (abbreviated Dextran:FITC; Molecular Probes) at 20 dpi (Table 1). Five animals received a second injection of Alexa Fluor 647econjugated dextran (abbreviated Dextran:AF647; Molecular Probes) 48 hours before necropsy to determine macrophage recruitment from 20 dpi necropsy.…”

“…Previous studies on the rate of perivascular macrophage turnover in rodents (approximately 8% per week, as determined in mouse bone marrow chimeras, and approximately 2% per week, as determined by serial dextran labeling in rats) indicate that the total population of perivascular macrophages is replaced over several months, although individual macrophages may reside in the CNS for years. 30,31,49,68 The slow turnover rate of perivascular macrophages in the CNS, some of which may be infected, likely contributes to the maintenance of a viral reservoir in the CNS with HIV or SIV infection. Previous research indicates that the number of activated macrophages in the CNS better correlates with HIV dementia than viral replication in the CNS.…”

Angiogenic Recruitment of Pericytes from Bone Marrow after Stroke

“…There are reports that pericytes can leave the endothelial basement membrane and migrate into the perivascular space (Dore-Duffy et al, 2000; Thomas, 1999), or into the brain parenchyma to give rise to resident microglia (Bechmann et al, 2001b). That pericytes, perivascular cells and microglia express an overlapping set of immunophenotypic markers has led many investigators to conclude that all three cell types are derived from a common monocyte progenitor (Guillemin and Brew, 2004;Thomas, 1999).…”

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

“…Age-related failure of perivascular drainage from the hippocampus may also be exacerbated by the continuous flow of solutes from the thalamus. Furthermore, the presence of an expandable perivascular space around thalamic arteries may help to counteract age-related decreases in the pulsatile forces that drive perivascular drainage and allow for greater exposure to perivascular macrophages that reside within perivascular spaces and mediate CAA severity (Zhang et al, 1990;Pollock et al, 1997;Bechmann et al, 2001;Hawkes & McLaurin, 2009).…”