The blood–brain barrier endothelium: a target for pro-inflammatory cytokines

Rochfort, Keith D.; Cummins, Philip M.

doi:10.1042/bst20140319

Cited by 177 publications

(141 citation statements)

References 49 publications

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“…Over the last 15 years, the concept that the BBB might function both as source and target of proinflammatory factors is supported by numerous studies showing that the cerebral microcirculation is in an “activated proinflammatory” stage in neurodegenerative diseases such as AD [15, 55] and is a target for various proinflammatory factors. PAUSE Circulating Aβ is a proinflammatory cytokine-induced DAMP that binds to RAGE and TLR2 [56].…”

Section: Discussionmentioning

confidence: 99%

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

Festoff

Sajja

Dreden

et al. 2016

J Neuroinflammation

160

123

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Background: The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients. Methods: We determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed the specific and direct effects of such molecules on BBB integrity in vitro using human primary brain microvascular endothelial cells or a cell line. Results: We observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects). Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients. In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients. Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands. Pre-treatment with anti-HMGB1 monoclonal antibody blocked HMGB1 effects and leaving BBB integrity intact. Conclusions: Our current studies indicate that thrombin and HMGB1 are causal proximate proinflammatory mediators of BBB dysfunction, while sTM levels may indicate BBB endothelial damage; HMGB1 and sRAGE might serve as clinical biomarkers for progression and/or therapeutic efficacy along the AD spectrum.

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Section: Discussionmentioning

confidence: 99%

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

Festoff

Sajja

Dreden

et al. 2016

J Neuroinflammation

160

123

View full text Add to dashboard Cite

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“…The understanding of TBI pathophysiology, particularly the intersecting roles of inflammation and oxidative stress, remains incomplete 42 . TBI results in endothelial activation, BBB damage and permeability 23, 42 , and the production of oxidative stress mediators that contribute to injury propagation in neurotrauma 42, 43 .…”

Section: Discussionmentioning

confidence: 99%

“…TBI results in endothelial activation, BBB damage and permeability 23, 42 , and the production of oxidative stress mediators that contribute to injury propagation in neurotrauma 42, 43 . While studies have shown heterogeneous efficacy of antioxidant therapy, a targeted enzymatic antioxidant approach to TBI management has not yet been explored.…”

Section: Discussionmentioning

confidence: 99%

Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury

Lutton

Razmpour

Andrews

et al. 2017

Sci Rep

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Traumatic brain injury (TBI) contributes to one third of injury related deaths in the US. Treatment strategies for TBI are supportive, and the pathophysiology is not fully understood. Secondary mechanisms of injury in TBI, such as oxidative stress and inflammation, are points at which intervention may reduce neuropathology. Evidence suggests that reactive oxygen species (ROS) propagate blood-brain barrier (BBB) hyperpermeability and inflammation following TBI. We hypothesized that targeted detoxification of ROS may improve the pathological outcomes of TBI. Following TBI, endothelial activation results in a time dependent increase in vascular expression of ICAM-1. We conjugated catalase to anti-ICAM-1 antibodies and administered the conjugate to 8 wk old C57BL/6J mice 30 min after moderate controlled cortical impact injury. Results indicate that catalase targeted to ICAM-1 reduces markers of oxidative stress, preserves BBB permeability, and attenuates neuropathological indices more effectively than non-targeted catalase and anti-ICAM-1 antibody alone. Furthermore, the study of microglia by two-photon microscopy revealed that anti-ICAM-1/catalase prevents the transition of microglia to an activated phenotype. These findings demonstrate the use of a targeted antioxidant enzyme to interfere with oxidative stress mechanisms in TBI and provide a proof-of-concept approach to improve acute TBI management that may also be applicable to other neuroinflammatory conditions.

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“…To the best of our knowledge, the regulation of this process by glucocorticoids had not been studied before. Our vitro model using DEX treated HUVEC and CORT treated rats to integrate the established observations that glucocorticoids can restrict paracellular transport across various endothelia (Keaney and Campbell 2015; Rao, et al 2015; Rochfort and Cummins 2015) with the fact that glucocorticoids, commonly prescribed medications, have numerous side effects, including insulin resistance and diabetes (Beaudry et al 2015). Furthermore, we examined whether the emerging phenomenon that transendothelial movement of Ad may regulate the anti-diabetic effects of this hormone and whether this was regulated by glucocorticoids (Rutkowski et al 2014; Yoon et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Transendothelial movement of adiponectin is restricted by glucocorticoids

Dang

Yoon

Chasiotis

et al. 2017

Journal of Endocrinology

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Altered permeability of the endothelial barrier in a variety of tissues has implications both in disease pathogenesis and treatment. Glucocorticoids are potent mediators of endothelial permeability and this forms the basis for their heavily-prescribed use as medications to treat ocular disease. However, the effect of glucocorticoids on endothelial barriers elsewhere in the body is less well-studied. Here we investigated glucocorticoid-mediated changes in endothelial flux of Adiponectin (Ad), a hormone with a critical role in diabetes. First, we used monolayers of endothelial cells in vitro and found that the glucocorticoid dexamethasone increased transendothelial electrical resistance and reduced permeability of polyethylene glycol (PEG, molecular weight 4000kDa). Dexamethasone reduced flux of Ad from the apical to basolateral side, measured both by ELISA and Western blotting. We then examined a diabetic rat model induced by treatment with exogenous corticosterone, which was characterized by glucose intolerance and hyperinsulinemia. There was no change in circulating Ad but less Ad protein in skeletal muscle homogenates, despite slightly higher mRNA levels, in diabetic versus control muscles. Dexamethasone-induced changes in Ad flux across endothelial monolayers were associated with alterations in the abundance of select claudin (CLDN) tight junction (TJ) proteins. shRNA-mediated knockdown of one such gene, claudin-7, in HUVEC resulted in decreased TEER and increased adiponectin flux, confirming the functional significance of Dex-induced changes in its expression. In conclusion, our study identifies glucocorticoid-mediated reductions in flux of Ad across endothelial monolayers in vivo and in vitro. This suggests that impaired Ad action in target tissues, as a consequence of reduced transendothelial flux, may contribute to the glucocorticoid-induced diabetic phenotype.

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The blood–brain barrier endothelium: a target for pro-inflammatory cytokines

Cited by 177 publications

References 49 publications

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury

Transendothelial movement of adiponectin is restricted by glucocorticoids

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