Novel insights into the development and maintenance of the blood–brain barrier

Engelhardt, Britta; Liebner, Stefan

doi:10.1007/s00441-014-1811-2

Cited by 247 publications

(243 citation statements)

References 106 publications

(122 reference statements)

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“…Endothelial barrier function in the CNS is induced by the canonical Wnt/␤-catenin pathway that regulates barrier-related genes in BBB microvessels (Engelhardt and Liebner, 2014). Although so far BBB research focused mostly on the regulation of junction molecules and transporter systems, metabolic pathways receive increasing attention in vascular biology and in CNS vessels (Eelen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function

et al. 2016

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The canonical Wnt/␤-catenin signaling pathway is crucial for blood-brain barrier (BBB) formation in brain endothelial cells. Although glucose transporter 1, claudin-3, and plasmalemma vesicular-associated protein have been identified as Wnt/␤-catenin targets in brain endothelial cells, further downstream targets relevant to BBB formation and function are incompletely explored. By Affymetrix expression analysis, we show that the cytochrome P450 enzyme Cyp1b1 was significantly decreased in ␤-catenin-deficient mouse endothelial cells, whereas its close homolog Cyp1a1 was upregulated in an aryl hydrocarbon receptor-dependent manner, hence indicating that ␤-catenin is indispensable for Cyp1b1 but not for Cyp1a1 expression. Functionally, Cyp1b1 could generate retinoic acid from retinol leading to cell-autonomous induction of the barrier-related ATP-binding cassette transporter P-glycoprotein. Cyp1b1 could also generate 20-hydroxyeicosatetraenoic acid from arachidonic acid, decreasing endothelial barrier function in vitro. In mice in vivo pharmacological inhibition of Cyp1b1 increased BBB permeability for small molecular tracers, and Cyp1b1 was downregulated in glioma vessels in which BBB function is lost. Hence, we propose Cyp1b1 as a target of ␤-catenin indirectly influencing BBB properties via its metabolic activity, and as a potential target for modulating barrier function in endothelial cells.

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Section: Discussionmentioning

confidence: 99%

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function

et al. 2016

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“…[25][26][27] During development, the Wnt signaling pathway is activated and induces BBB maturation through the up-regulation of claudin-3 and the concomitant decrease of PV1 expression. 28 Since PV1 modulation is regulated by Wnt/b-catenin pathway and we found that Salmonella is able to induce PV1 expression, we hypothesized that b-catenin activation may be also involved in the maintenance of the GVB and that Salmonella may be capable of interfering with this pathway.…”

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confidence: 99%

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

et al. 2016

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It has been widely demonstrated that tolerance against gut microbiota is compartmentalized to mucosal sites where microbes mostly reside. How the commensal bacteria are excluded from the entrance into the blood stream via intestinal capillaries that are located beneath the gut epithelium was not clear. We recently described the existence of a new anatomical structure, the 'gut vascular barrier' (GVB), both in murine and human intestines that plays a fundamental role in avoiding indiscriminate trafficking of bacteria from the gut into the blood circulation. The vascular barrier integrity could be altered by Salmonella typhimurium, a pathogen capable of systemic dissemination, through the modulation of the Wnt/b-catenin signaling pathway. Here we have analyzed the differences in gut endothelial gene expression profiles during Salmonella infection and have identified some interesting characteristics of endothelial to mesenchymal transition. These findings add new insights in the gut-liver axis. The intestine is continuously exposed to a huge amount of foreign antigens, mostly food proteins and commensal microorganisms. These harmless antigens induce oral tolerance, which is however different when considering gut bacteria or food antigens. Tolerance to food proteins affects both local and systemic immune responses 1 indeed fed soluble antigens can gain access to the lymphatics to reach the mesenteric lymph nodes (mLN) 2 and the blood stream to reach the liver 3 where oral tolerance is established. By contrast, gut microbes are confined at mucosal sites by the mLNs that function like a firewall avoiding the spreading of intestinal microflora through the thoracic duct into the blood circulation. [4][5][6] Therefore at steady state the systemic immune system is left ignorant to the microbiota. Only during intestinal pathology bacteria can reach the liver that acts as a firewall preventing the bacteria from spreading to other systemic sites. 7 How the microbiota recirculates through the lymphatics has been widely studied, while how intestinal bacteria are excluded from the blood circulation was completely unexplored, even though it is known that intestinal capillaries are located just underneath the epithelial layer whereas the lymphatics are much deeper in the lamina propria.In our recent work, we hypothesized the existence of a barrier at the endothelial level, the 'gut vascular barrier' (GVB), 8 that similarly to the blood brain barrier (BBB) is able to control the type of antigens that can translocate into the blood stream and that is not permissive to bacterial penetration.Drawing a parallelism between the well-known BBB and the newly identified GVB many similarities can be found. Both are able to avoid the indiscriminate movement of molecules, cells and bacteria from blood to the brain parenchyma in the BBB and from the intestinal lumen into the blood circulation in the case of the GVB.

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“…The BBB regulates access of molecules and cells to the brain parenchyma from the circulation, maintaining homeostasis and protecting the brain from pathogens (8,9). Microvascular endothelial cells are the main functional component of the BBB.…”

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confidence: 99%

“…Microvascular endothelial cells are the main functional component of the BBB. Endothelial cells (ECs) are tightly linked to one another through tight-junction proteins, and the BBB endothelium is distinct from other endothelium in the body due to interactions with other cells, particularly astrocytes, and noncellular elements (8). Astrocytes are glial cells that comprise more than 50% of the total cells in the brain (9).…”

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confidence: 99%

Matrix Metalloproteinase Activity in Infections by an Encephalitic Virus, Mouse Adenovirus Type 1

Ashley

Pretto

Stier

et al. 2017

J Virol

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Mouse adenovirus type 1 (MAV-1) infection causes encephalitis in susceptible strains of mice and alters the permeability of infected brains to small molecules, which indicates disruption of the blood-brain barrier (BBB). Under pathological conditions, matrix metalloproteinases (MMPs) can disrupt the BBB through their proteolytic activity on basement membrane and tight junction proteins. We examined whether MAV-1 infection alters MMP activity in vivo and in vitro. Infected MAV-1-susceptible SJL mice had higher MMP2 and MMP9 activity in brains, measured by gelatin zymography, than mock-infected mice. Infected MAV-1-resistant BALB/c mice had MMP activity levels equivalent to those in mock infection. Primary SJL mouse brain endothelial cells (a target of MAV-1 in vivo) infected ex vivo with MAV-1 had no difference in activities of secreted MMP2 and MMP9 from mock cells. We show for the first time that astrocytes and microglia are also infected in vivo by MAV-1. Infected mixed primary cultures of astrocytes and microglia had higher levels of MMP2 and MMP9 activity than mock-infected cells. These results indicate that increased MMP activity in the brains of MAV-1-infected susceptible mice may be due to MMP activity produced by endothelial cells, astrocytes, and microglia, which in turn may contribute to BBB disruption and encephalitis in susceptible mice.IMPORTANCE RNA and DNA viruses can cause encephalitis; in some cases, this is accompanied by MMP-mediated disruption of the BBB. Activated MMPs degrade extracellular matrix and cleave tight-junction proteins and cytokines, modulating their functions. MAV-1 infection of susceptible mice is a tractable small-animal model for encephalitis, and the virus causes disruption of the BBB. We showed that MAV-1 infection increases enzymatic activity of two key MMPs known to be secreted and activated in neuroinflammation, MMP2 and MMP9, in brains of susceptible mice. MAV-1 infects endothelial cells, astrocytes, and microglia, cell types in the neurovascular unit that can secrete MMPs. Ex vivo MAV-1 infection of these cell types caused higher MMP activity than mock infection, suggesting that they may contribute to the higher MMP activity seen in vivo. To our knowledge, this provides the first evidence of an encephalitic DNA virus in its natural host causing increased MMP activity in brains.

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Novel insights into the development and maintenance of the blood–brain barrier

Cited by 247 publications

References 106 publications

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

Matrix Metalloproteinase Activity in Infections by an Encephalitic Virus, Mouse Adenovirus Type 1

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