Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

Ogunshola, Omolara O.; Moransard, Martijn; Gassmann, Max

doi:10.1016/j.brainres.2013.07.033

Cited by 10 publications

(6 citation statements)

References 40 publications

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“…Similarly, a transgenic murine model of excessive erythrocytosis demonstrated co‐elevation of TNF‐α and IL‐6 within brain and plasma, concomitant with increased BBB permeability and reduced occludin expression (Ogunshola et al . ). Co‐elevated levels of TNF‐α and IL‐6 within the neurovascular unit has also been linked to cerebral infarction in rats (Sirén et al .…”

Section: Discussionmentioning

confidence: 97%

Tumour necrosis factor‐α‐mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin‐6

Rochfort

Collins

McLoughlin

et al. 2015

Journal of Neurochemistry

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The co-involvement of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) during blood-brain barrier (BBB) injury has been reported in various models of neuroinflammation, although the precise functional interplay between these archetypal proinflammatory cytokines remains largely undefined within this context. In the current paper, we tested the hypothesis that TNF-α-mediated BBB disruption is measurably attributable in-part to induction of microvascular endothelial IL-6 production. In initial experiments, we observed that treatment of human brain microvascular endothelial cells (HBMvECs) with TNF-α (0-100 ng/mL, 0-24 h) robustly elicited both time- and dose-dependent induction of IL-6 expression and release, as well as expression of the IL-6 family receptor, GP130. Further experiments demonstrated that the TNF-α-dependent generation of reactive oxygen species, down-regulation of adherens/tight junction proteins, and concomitant elevation of HBMvEC permeability, were all significantly attenuated by blockade of IL-6 signalling using either an anti-IL-6 neutralizing antibody or an IL-6 siRNA. Based on these observations, we conclude that TNF-α treatment of HBMvECs in vitro activates IL-6 production and signalling, events that were shown to synergize with TNF-α actions to elicit HBMvEC permeabilization. These novel findings offer a constructive insight into the specific contribution of downstream cytokine induction to the injurious actions of TNF-α at the BBB microvascular endothelium interface. The co-involvement of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) during blood-brain barrier (BBB) injury has been widely reported. Using human brain microvascular endothelial cells (HBMvEC), we show that TNF-α-mediated BBB disruption is measurably attributable in-part to induction of endothelial IL-6 production and signalling. We demonstrate that the TNF-α-dependent generation of reactive oxygen species (ROS), down-regulation of interendothelial junctions, and concomitant elevation of HBMvEC permeability, could be significantly attenuated by using either an IL-6 neutralizing antibody or an IL-6-specific siRNA. These findings provide insight into the complex nature of proinflammatory cytokine injury at the BBB microvascular endothelium interface.

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Section: Discussionmentioning

confidence: 97%

Tumour necrosis factor‐α‐mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin‐6

Rochfort

Collins

McLoughlin

et al. 2015

Journal of Neurochemistry

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“…Intracellular junctional proteins have been elucidated to maintain the cell-cell barrier [ 52 , 53 ]. Degradation of the AJ protein β -catenin [ 54 , 55 ] interferes with the sealing efficiency of ECs and results in barrier disruption. Our study revealed that activation of Sirt1 reversed LPS-sparked loss of β -catenin, while inactivation of Sirt1 exacerbated the effect.…”

Section: Discussionmentioning

confidence: 99%

Sirt1 Protects Endothelial Cells against LPS‐Induced Barrier Dysfunction

Zhang

Guo

et al. 2017

Oxidative Medicine and Cellular Longevity

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Sepsis is a threatening health problem and characterized by microvascular dysfunction. In this study, we verified that LPS caused the downregulation of Sirt1 and the hyperpermeability of endothelial cells. Inhibition of Sirt1 with ex527 or Sirt1 siRNA displayed a higher permeability, while activation of Sirt1 with SRT1720 reversed the LPS-induced hyperpermeability, formation of fiber stress, and disruption of VE-cadherin distribution. In pulmonary microvascular vein endothelial cells isolated from wild-type mice, Sirt1 was attenuated upon LPS, while Sirt1 was preserved in a receptor of advanced glycation end product-knockout mice. The RAGE antibody could also diminish the downregulation and ubiquitination of Sirt1 in LPS-exposed human umbilical vein endothelial cells. An LPS-induced decrease in Sirt1 activity was attenuated by the RAGE antibody and TLR4 inhibitor. In vivo study also demonstrated the attenuating role of Sirt1 and RAGE knockout in LPS-induced increases in dextran leakage of mesenteric venules. Furthermore, activation of Sirt1 prevented LPS-induced decreases in the activity and expression of superoxide dismutase 2, as well as the increases in NADPH oxidase 4 and reactive oxygen species, while inhibition of Sirt1 aggravated the SOD2 decline. It also demonstrated that Sirt1-deacetylated p53 is required for p53 inactivation, which reversed the downregulation of β-catenin caused by LPS.

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“…mTOR signalling can promote cancer stem cell growth and has been correlated with chemotherapy resistance of breast cancer cells with stem cell characteristics . In regards to the association of mTOR with other proliferative mechanisms, growth factors that rely upon mTOR signalling, such as EPO, may lead to cancer and blood–brain barrier injury during prolonged treatment regimens. Down‐stream signalling pathways of EPO, such as Wnt and WISP1, also can lead to unchecked cellular growth.…”

Section: Future Perspectivesmentioning

confidence: 99%

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Maiese¹

2015

Brit J Clinical Pharma

161

122

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Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3‐kinase (PI 3‐K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.

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Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

Cited by 10 publications

References 40 publications

Tumour necrosis factor‐α‐mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin‐6

Tumour necrosis factor‐α‐mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin‐6

Sirt1 Protects Endothelial Cells against LPS‐Induced Barrier Dysfunction

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

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