Claudin-1 induced sealing of blood–brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis

Pfeiffer, Friederike; Schäfer, Julia; Lyck, Ruth; Makrides, Victoria; Brunner, Sarah; Schaeren‐Wiemers, Nicole; Deutsch, Urban; Engelhardt, Britta

doi:10.1007/s00401-011-0883-2

Cited by 132 publications

(118 citation statements)

References 51 publications

(81 reference statements)

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“…Regardless of the low expression, CLDN1 function in human brain capillaries is critical for the maintenance of the BBB integrity during neuroinflammation and brain tumor 29, 44. In the experimental model of EAE, the induced expression of CLDN1 in only 30% to 50% of brain vasculature was sufficient for BBB strengthening and significant amelioration of the disease 45. Based on these studies and our own data, we propose that increased expression of CLDN1 and ZO‐1 after miR‐155 inhibition significantly contribute to the stabilization of HBMECs monolayer after OGD.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Section: Discussionmentioning

confidence: 99%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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“…ECs are the major components of the BBB, and TJ proteins present on and between the ECs form a barrier that maintains the homeostasis of the CNS by restricting the diffusion of bloodborne molecules (38). Alteration of TJ protein expression has been observed in viral infections (MAV-1) or autoimmune diseases (EAE) (26,28).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Chai

Wen

Zhou

et al. 2014

J Virol

147

135

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Infection with laboratory-attenuated rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival, since it allows immune effectors to enter the central nervous system (CNS) and clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expression of tight junction (TJ) proteins in the CNS was investigated following intracranial inoculation with laboratory-attenuated or wild-type (wt) RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins (claudin-5, occludin, and zonula occludens-1) were decreased in mice infected with laboratoryattenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with the reduction of TJ protein expression in RABV infection. RABV neither infects the brain microvascular endothelial cells (BMECs) nor modulates the expression of TJ proteins in BMECs. However, brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expression in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that gamma interferon (IFN-␥) is located in the center of the cytokine network in the RABV-infected mouse brain, and neutralization of IFN-␥ reduced both the disruption of BBB permeability in vivo and the downregulation of TJ protein expression in vitro. These findings indicate that the enhancement of BBB permeability and the reduction of TJ protein expression are due not to RABV infection per se but to virus-induced inflammatory chemokines/cytokines. IMPORTANCEPrevious studies have shown that infection with only laboratory-attenuated, not wild-type, rabies virus (RABV) enhances bloodbrain barrier (BBB) permeability, allowing immune effectors to enter the central nervous system (CNS) and clear RABV from the CNS. This study investigated the mechanism by which RABV infection enhances BBB permeability. It was found that RABV infection enhances BBB permeability by downregulation of tight junction (TJ) protein expression in the brain microvasculature. It was further found that it is not RABV infection per se but the chemokines/cytokines induced by RABV infection that downregulate the expression of TJ proteins and enhance BBB permeability. Blocking some of these cytokines, such as IFN-␥, ameliorated both the disruption of BBB permeability and the downregulation of TJ protein expression. These studies may provide a foundation for developing therapeutics for clinical rabies, such as medication that could be used to enhance BBB permeability.

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“…FH-BNBs showed spindle fiber morphology and contact inhibition even under the permissive temperature of 33°C, indicating that FH-BNBs, even at the permissive temperature, did not develop a tumor-like phenotype. The endothelial cells forming the BBB express many TJassociated molecules including occludin (Furuse et al, 1993), claudin-1 (Pfeiffer et al, 2011), claudin-5 (Nitta et al, 2003, claudin-12 (Nitta et al, 2003;Ohtsuki et al, 2007), ZO-1, ZO-2 (Biernacki et al, 2004) and JAM-A (Yeung et al, 2008). These molecules compose TJs and limit the paracellular permeability in order to maintain the brain microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of Human Peripheral Nerve Microvascular Endothelial Cell Lines: A New <i>in vitro</i> Blood-Nerve Barrier (BNB) Model

Abe

Sano

Maeda

et al. 2012

Cell Struct. Funct.

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ABSTRACT. The blood-nerve barrier (BNB) is a highly specialized unit that maintains the microenvironments of the peripheral nervous system. Since the breakdown of the BNB has been considered a key step in autoimmune neuropathies such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyraduculoneuropathy, it is important to understand the cellular properties of the peripheral nerve microvascular endothelial cells (PnMECs) which constitute the BNB. For this purpose, we established an immortalized cell line derived from human PnMECs. The human PnMECs were transduced with retroviral vectors encoding the temperaturesensitive SV40 large T antigen and human telomerase. This cell line, termed FH-BNB, showed a spindle fibershaped morphology, expression of von Willebrand factor and uptake of acetylated low density lipoprotein. These cells expressed tight junction proteins including occludin, claudin-5, ZO-1 and ZO-2 at the cell-cell boundaries. P-glycoprotein and GLUT-1 were also detected by a Western blot analysis and the cells exhibited the functional expression of p-glycoprotein. In addition, transendothelial electrical resistance experiments and paracellular permeabilities of sodium fluorescein and fluorescein isothiocyanate-labeled dextran of molecular weight 4 kDa across these cells demonstrated that FH-BNBs had functional tight junctions. These results indicated that FHBNBs had highly specialized barrier properties and they might therefore be a useful tool to analyze the pathophysiology of various neuropathies.

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Claudin-1 induced sealing of blood–brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis

Cited by 132 publications

References 51 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Establishment and Characterization of Human Peripheral Nerve Microvascular Endothelial Cell Lines: A New <i>in vitro</i> Blood-Nerve Barrier (BNB) Model

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