Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

Abstract

The blood-brain barrier (BBB) is a selectively permeable barrier separating the periphery from the central nervous system (CNS). The BBB restricts the flow of most material into and out of the CNS, including many drugs that could be used as potent therapies. BBB permeability is modulated by several cells that are collectively called the neurovascular unit (NVU). The NVU consists of specialized CNS endothelial cells (ECs), pericytes, astrocytes, microglia, and neurons. CNS ECs maintain a complex "seal" via tight junctions, forming the BBB; breakdown of these tight junctions leads to BBB disruption. Pericytes control the vascular flow within capillaries and help maintain the basal lamina. Astrocytes control much of the flow of material that has moved beyond the CNS EC layer and can form a secondary barrier under inflammatory conditions. Microglia survey the border of the NVU for noxious material. Neuronal activity also plays a role in the maintenance of the BBB. Since astrocytes, pericytes, microglia, and neurons are all able to modulate the permeability of the BBB, understating the complex contributions of each member of the NVU will potentially uncover novel and effective methods for delivery of neurotherapies to the CNS.

Keywords: blood-brain barrier; endothelial cell; glia; neuroinflammatory disease; pericyte; tight junction.

FIGURE 1

Cellular components of the neurovascular unit. The NVU is composed of a complex network of cells that are functionally diverse. ECs form the walls of blood vessels and capillaries and contribute to the formation and maintenance of the basal lamina and extracellular matrix. In addition, tight junctions formed between ECs and expression of adhesion molecules regulate BBB permeability. Pericytes reside in the capillary bed and, with regard to BBB integrity, are primarily responsible for modulation of vascular flow as well as structural changes in tight junctions and the extracellular matrix. Astrocyte endfeet cover 90%–95% of the area surrounding the BBB and contribute to a variety of processes that include, but are not limited to, osmotic homeostasis, trophic factor concentration, molecular transport into and out of the perivascular space, and formation of gap junctions under neuroinflammatory conditions. Microglia have been found to cover the remaining space around BBB ECs, respond to injury and infection, and regulate tight junction formation between ECs. Neurons predominantly communicate with astrocyte endfeet and aid in regulation of tight junctions and molecular transport.

FIGURE 2

NVU interaction network. Cells within the NVU interact through intricate signaling mechanisms that allow for proper functioning of the BBB. ECs receive a variety of protective signals from other NVU cells that upregulate tight junction formation thus enhancing BBB integrity. These factors include, but are not limited to, TGFβ, Ang‐1, APOE, Shh, Wnts, glial‐derived neurotrophic factor, insulin‐like growth factor (IGF)‐1, and retinoic acid. Contrastingly, ECs may also receive signals that downregulate tight junction proteins, particularly during inflammatory events, such as TNFα, NO, MMPs, endothelins, and glutamate that lead to increased BBB permeability. Importantly, ECs also maintain the ability to signal to pericytes through VEGF and N‐cadherin, which are necessary for BBB maintenance. Immune checkpoint proteins, such as the PD‐1/PD‐L1 complex, regulate the cellular activity of microglia and neurons to modulate BBB integrity as well as dampen the inflammatory activity of infiltrating peripheral immune cells, which increases BBB permeability. Finally, neuronal activity is a critical modulator of cellular and molecular transport across the BBB.