Brain perivascular macrophages: characterization and functional roles in health and disease

Abstract

Perivascular macrophages (PVM) are a distinct population of resident brain macrophages characterized by a close association with the cerebral vasculature. PVM migrate from the yolk sac into the brain early in development and, like microglia, are likely to be a self-renewing cell population that, in the normal state, is not replenished by circulating monocytes. Increasing evidence implicates PVM in several disease processes, ranging from brain infections and immune activation to regulation of the hypothalamic-adrenal axis and neurovascular-neurocognitive dysfunction in the setting of hypertension, Alzheimer disease pathology, or obesity. These effects involve crosstalk between PVM and cerebral endothelial cells, interaction with circulating immune cells, and/or production of reactive oxygen species. Overall, the available evidence supports the idea that PVM are a key component of the brain-resident immune system with broad implications for the pathogenesis of major brain diseases. A better understanding of the biology and pathobiology of PVM may lead to new insights and therapeutic strategies for a wide variety of brain diseases.

Keywords: Alzheimer’s disease; Brain perivascular macrophages; CNS infections; Cerebrovascular regulation; Immune-to-brain signaling.

Fig. 1

Anatomical localization of perivascular (PVM) and meningeal macrophages (MGM). a PVM are located in the perivascular space surrounding arteries and veins as they penetrate deeply into the brain tissue, whereas MGM can be found in association with the meninges. The perivascular space is delimited by the vascular basement membrane (vascular BM) on the abluminal side of the vessel wall and by the glia limitans basement membrane (glial BM) on the parenchymal side. At the level of smaller arterioles (≤ 10 μM) and capillaries, the two membranes fuse together occluding the perivascular space. b PVM can be identified as perivascular cells positive for CD206 (arrows). c Flat mount preparation of the meninges. MGM are CD206 positive and, like PVM, are able to phagocytose i.c.v-injected TRITC-dextran (arrowheads). MSM also express the endothelial lymphatic vessel marker LYVE1 (arrows). Scale bars 50 μM. EC endothelial cells, SMC smooth muscle cells, i.c.v. intracerebral ventricular

Fig. 2

Selected roles of PVM in the brain. PVM have been implicated in (1) the neurovascular and cognitive dysfunction induced by hypertension, (2) the influx of PMN in viral and bacterial infections of the CNS, (3) the clearance of amyloid-β peptides and the neurovascular dysfunction in AD, (4 and 5) and the regulation of the HPA axis associated with systemic inflammation induced by pro-inflammatory agents, e.g., LPS, or myocardial infarction. ROS reactive oxygen species, NO nitric oxide, PMN polymorphonuclear cells, ANGII angiotensin II, AD Alzheimer’s disease, HPA hypothalamic-pituitary axis, MI myocardial infarction