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Transport Across the BBB

The BBB prevents the passive entry of water, charged solutes, soluble mediators (including circulating neurotransmitters), proteins (immunoglobulins, cytokines, chemokines), and immune cells in the peripheral circulation into the CNS, protecting it from unintended immune activation and excitotoxic stress. BBB homeostasis is a prerequisite for normal neuron functioning; neurons are extremely sensitive to fluctuations in parenchymal ionic strength (Ca2+, Na+, K+). Although limited immune cell exchange across the BBB is normal, a low continuous level of immune cell surveillance protects the brain against viral (e.g., JC virus) reactivation and is a consequence of BBB immune suppression and MS therapy.

Among the cells forming the BBB, CEC lines the intimal surface of larger cerebral vessels and are the major component of brain capillaries. The highly specialized CEC establishes physical barriers against the exchange of solutes, ions, and formed blood elements. Trans-BBB exchange of immune cells can take place tran- scellularly (penetrating the endothelial cytoplasm) or at inter-CEC junctions (para- cellularly) as is found in most other endothelia [1]. The “decision” for immune cells to either pathway reflects the level of expression and context for presentation of intercellular adhesion molecule-1 (ICAM-1) [1]. The ICAM-1 cytoplasmic domain appears to be absolutely required for Rho-mediated signaling, which leads to cyto- skeletal rearrangements necessary for T cell penetration of the CEC [2]. Gorina et al. (2014) have suggested that both neutrophil “crawling” mediated by ICAM-1 and ICAM-2 are necessary events leading to BBB extravasation [3]. von Wedel- Parlow and colleagues have suggested that neutrophils can pass across BBB endothelium transcellularly without disturbing the junctional barrier [4], although perturbations in tight and adherens junction binding and organization can increase extravasation at this route as well [5, 6]. Consequently, both tight and adherens junctional organization as well as adhesion molecule expression can influence trans- BBB immune cell exchange.

This BBB restriction to cells and solute exchange is achieved by cooperative interactions between tight junctions (TJs) and adherens junctions (AJs) between apposed endothelial cells. These interactions allow the BBB to create an electrically resistive barrier of up to 1500 ohms/cm2 (known as “gate” function). The lateral sealing of apical and basolateral membrane domains (“fence” function) [7, 8] segregates luminal and abluminal adhesion molecules, transporter and matrix binding, and cell contact domains. BBB establishment and development depend on several paracrine signals from astrocytes and glia to the endothelium; neurons may also indirectly influence BBB. Astrocyte-derived brain-derived neurotrophic factor (BDNF) [9], platelet-derived growth factor-p (PDGF-BB), pericyte-derived transforming growth factor-p (TGF-p), GDNF, bFGF, IL-6, and steroids [10, 11] all contribute to the establishment and organization of the BBB [11, 12]. PDGF-p stabilizes BBB phenotype by recruiting pericytes to the BBB [13]. Pericytes in turn continuously release TGF-p, which establishes and induces the BBB by inducing transcription of claudin-5, an important component of TJ [11]. The actual physical barrier of the BBB occurs at the molecular level of the tight junctions, which is supported by adherens junctions, between adjacent BECs, which is regulated by these factors. Although pericyte TGF-p may help to establish BBB, ischemic pericyte release of VEGF-A can also trigger vascular leakage [14], illustrating the complexity of the “support” cells, which are able to both enhance and disintegrate the BBB. Astrocytes significantly upregulate VEGF expression during MS [15], which in turn downregu- lates claudin-5 and occludin levels by activating p38 mitogen-activated protein kinase (MAPK) [16]. Astrocytes are instrumental in MS neuroinflammation, not only due to the release of factors that disrupt the BBB but also because the loss of its polarity can also cause BBB dysfunction. Loss of polarized expression of aqua- porin 4 (AQP4) in the astrocytic foot processes is seen in an animal model of MS, experimental allergic encephalomyelitis (EAE) [17]. Loss of astrocytic polarity suggests that the polarized secretion of various astrocytic-derived factors (e.g., sonic hedgehog (Hh)) is also compromised in experimental and clinical MS. Astrocytes secrete Hh and bind Hh receptors expressed on BBB endothelial cells to promote BBB formation and integrity [18]. Hh is upregulated in active demyelinating lesions and is correlated with increased Hh receptor expression in BBB endothelial cells, indicating a possible compensatory mechanism to promote BBB repair.

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