Immunology of Brain Endothelium and the Blood-Brain Barrier

1992 ◽  
pp. 397-415 ◽  
Author(s):  
D. K. Male
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Blood Brain

scholarly journals Comparison of polypeptides that bind the transferrin receptor for targeting gold nanocarriers

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252341
Author(s):  
Conor McQuaid ◽  
Andrea Halsey ◽  
Maëva Dubois ◽  
Ignacio Romero ◽  
David Male
Keyword(s):  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Therapeutic Agents ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Linear Peptide ◽  
Blood Brain ◽  
Dividing Cells

The ability to target therapeutic agents to specific tissues is an important element in the development of new disease treatments. The transferrin receptor (TfR) is one potential target for drug delivery, as it expressed on many dividing cells and on brain endothelium, the key cellular component of the blood-brain barrier. The aim of this study was to compare a set of new and previously-described polypeptides for their ability to bind to brain endothelium, and investigate their potential for targeting therapeutic agents to the CNS. Six polypeptides were ranked for their rate of endocytosis by the human brain endothelial cell line hCMEC/D3 and the murine line bEnd.3. One linear polypeptide and two cyclic polypeptides showed high rates of uptake. These peptides were investigated to determine whether serum components, including transferrin itself affected uptake by the endothelium. One of the cyclic peptides was strongly inhibited by transferrin and the other cyclic peptide weakly inhibited. As proof of principle the linear peptide was attached to 2nm glucose coated gold-nanoparticles, and the rate of uptake of the nanoparticles measured in a hydrogel model of the blood-brain barrier. Attachment of the TfR-targeting polypeptide significantly increased the rates of endocytosis by brain endothelium and increased movement of nanoparticles across the cells.

scholarly journals miR-98 and let-7g* Protect the Blood-Brain Barrier Under Neuroinflammatory Conditions

2015 ◽  
Vol 35 (12) ◽  
pp. 1957-1965 ◽  
Author(s):  
Slava Rom ◽  
Holly Dykstra ◽  
Viviana Zuluaga-Ramirez ◽  
Nancy L Reichenbach ◽  
Yuri Persidsky
Keyword(s):  
Blood Brain Barrier ◽  
Glycogen Synthase ◽  
Leukocyte Adhesion ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
In Vivo Models ◽  
Blood Brain ◽  
Microarray Screening

Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier ‘leakiness’ in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.

scholarly journals Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

2014 ◽  
Vol 35 (1) ◽  
pp. 28-36 ◽  
Author(s):  
Slava Rom ◽  
Viviana Zuluaga-Ramirez ◽  
Holly Dykstra ◽  
Nancy L Reichenbach ◽  
Servio H Ramirez ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Parp Inhibition ◽  
Inflammatory Factors ◽  
In Vivo Model ◽  
Brain Endothelium ◽  
Monocyte Migration ◽  
Blood Brain ◽  
And Migration

Blood—brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte—endothelium interactions by intravital videomicroscopy. Poly(ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80–100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation.

scholarly journals Suppression of transcytosis regulates zebrafish blood-brain barrier function

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Natasha M O'Brown ◽  
Sean G Megason ◽  
Chenghua Gu
Keyword(s):  
Electron Microscopy ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Model Organism ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Developmental Profile ◽  
Developmental Program ◽  
Blood Brain ◽  
Optically Transparent

As an optically transparent model organism with an endothelial blood-brain barrier (BBB), zebrafish offer a powerful tool to study the vertebrate BBB. However, the precise developmental profile of functional zebrafish BBB acquisition and the subcellular and molecular mechanisms governing the zebrafish BBB remain poorly characterized. Here, we capture the dynamics of developmental BBB leakage using live imaging, revealing a combination of steady accumulation in the parenchyma and sporadic bursts of tracer leakage. Electron microscopy studies further reveal high levels of transcytosis in brain endothelium early in development that are suppressed later. The timing of this suppression of transcytosis coincides with the establishment of BBB function. Finally, we demonstrate a key mammalian BBB regulator Mfsd2a, which inhibits transcytosis, plays a conserved role in zebrafish, as mfsd2aa mutants display increased BBB permeability due to increased transcytosis. Our findings indicate a conserved developmental program of barrier acquisition between zebrafish and mice.

scholarly journals Non-Human Primate Blood–Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 967
Author(s):  
Catarina Chaves ◽  
Tuan-Minh Do ◽  
Céline Cegarra ◽  
Valérie Roudières ◽  
Sandrine Tolou ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Structures ◽  
Brain Regions ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Slc Transporters ◽  
Blood Brain ◽  
The Brain ◽  
Human Primate

The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood–brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were Investig.igated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.

scholarly journals Targeting nanoparticles to the brain by exploiting the blood–brain barrier impermeability to selectively label the brain endothelium

2020 ◽  
Vol 117 (32) ◽  
pp. 19141-19150 ◽  
Author(s):  
Daniel Gonzalez-Carter ◽  
Xueying Liu ◽  
Theofilus A. Tockary ◽  
Anjaneyulu Dirisala ◽  
Kazuko Toh ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Target Proteins ◽  
Blood Brain ◽  
Brain Microvasculature ◽  
The Brain

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood–brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal “off-target” accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.

scholarly journals Combination of HIV-1 and Diabetes Enhances Blood Brain Barrier Injury via Effects on Brain Endothelium and Pericytes

2020 ◽  
Vol 21 (13) ◽  
pp. 4663
Author(s):  
Slava Rom ◽  
Sachin Gajghate ◽  
Malika Winfield ◽  
Nancy L. Reichenbach ◽  
Yuri Persidsky
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Hiv Replication ◽  
Cellular Targets ◽  
Blood Brain ◽  
Brain Pericytes ◽  
Replication Control

Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV-associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. Blood brain barrier (BBB) dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. In this report, we found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND when compared to HIV-infected patients without DM or seronegative DM patients. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules in primary human brain endothelial cells or human brain pericytes after exposure to HIV and DM-relevant stimuli. Our study demonstrates for the first-time evidence of impaired BBB function in HIV-DM patients and shows potential mechanisms leading to it in brain endothelium and pericytes that may result in poorer cognitive performance compared to individuals without HIV and DM.

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