The blood-brain barrier (BBB) provides both anatomical and physiological protection for the central nervous system (CNS), strictly regulating the entry of many substances and blood borne cells into the nervous tissue. Increased understanding of how the unique microenvironment in the CNS influences the BBB is crucial for developing novel therapeutic approaches to CNS diseases. In this review, we discuss those characteristics of the BBB that play an important role in maintaining immune privilege in the CNS, as well as factors that regulate immune cell invasion through the BBB and thereby modulate immune responses in the nervous tissue. In general, immune cell invasion across the BBB is highly restricted and carefully regulated. A florid invasion of activated white blood cells can create a predominantly proinflammatory local environment in the CNS, leading to immune-mediated diseases of the nervous tissue. Recent developments in cellular and molecular biological methods have allowed closer analysis of BBB function, and led to an improved understanding of the active role of the BBB in immune-mediated diseases of the CNS.
Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin − 5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.
SummaryCurrent therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.
Recent evidence from this laboratory indicated that reduced expression of caveolin-1 accompanied the diminished expression of tight junction (TJ)-associated proteins occludin and zonula occludens-1 (ZO-1) following stimulation of brain microvascular endothelial cells (BMECs) with the chemokine CCL2 (formerly called MCP-1). Because attenuated caveolin-1 levels have also been correlated with heightened permeability of other endothelia, the objective of this study was to test the hypothesis that reduced caveolin-1 expression is causally linked to the action of CCL2 on BMEC junctional protein expression and barrier integrity. This was achieved using adenovirus to nondestructively deliver caveolin-1 siRNA (Ad-siCav-1) to BMEC monolayers, which model the blood-brain barrier (BBB). Treatment with siRNA reduced the caveolin-1 protein level as well as occludin and ZO-1. Additionally, occludin exhibited dissociation from the cytoskeletal framework. These changes were attended by comparable alterations in adherens junction (AJ)-associated proteins, VE-cadherin and -catenin, increased BMEC paracellular permeability, and facilitated the ability of CCL2 to stimulate monocytic transendo- IntroductionElevated permeability of the normally highly restrictive bloodbrain barrier (BBB) accompanies a variety of central nervous system (CNS) afflictions, including inflammation, infection, ischemia, seizures, and trauma. [1][2][3][4][5][6] Nevertheless, mechanisms regulating BBB permeability in physiological and pathophysiological situations remain poorly defined. Among the many factors affecting BBB permeability, this laboratory recently reported that the beta-chemokine CCL2 (formerly known as monocyte chemoattractant protein-1 [MCP-1]), which is elevated in the CNS during a variety of neuroinflammatory conditions, 7-10 plays an influential role. 11 Specifically, it effects dissociation of tight junction (TJ)-associated proteins occludin and zonula occludens-1 (ZO-1) from the cytoskeletal framework of brain microvascular endothelial cells (BMECs) comprising the BBB as well as diminished expression of these proteins. Given the proposed role(s) of TJs in restricting solute and cellular passage across endothelial and epithelial barriers, 12-14 such action could conceivably lie, in part, at the basis of the altered BBB permeability and accumulation of leukocytes in the CNS observed in certain neuroinflammatory episodes.Aside from the loss of occludin and ZO-1 following BMEC exposure to CCL2, expression of caveolin-1 was also significantly down-regulated. 11 This additional chemokine-associated loss may further contribute to BBB alteration, because caveolin-1 is the major structural protein of caveolae, membrane microdomains critically involved in various aspects of vesicular trafficking and cell signaling. [15][16][17] Of particular significance in this regard, Nusrat et al 18 reported that both occludin and ZO-1 might be organized within TJs by association with caveolin-1 in detergent-insoluble glycolipid rafts, membrane specializations...
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