Inflammatory events at blood–brain barrier in neuroinflammatory and neurodegenerative disorders: Implications for clinical disease

Vries, Helga E. de; Kooij, Gijs; Frenkel, Daan; Georgopoulos, Spiros; Monsonego, Alon; Janigro, Damir

doi:10.1111/j.1528-1167.2012.03702.x

Cited by 100 publications

(81 citation statements)

References 92 publications

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“…Knowing that increased BBB permeability under several insult conditions can occur through different mechanisms, 2,7 we further aimed to clarify what type of transport across ECs was being modulated by this TNF-α/NF-κB pathway. In fact, it was previously shown that METH increased both paracellular 5,9 and vesicular transport.…”

Section: Discussionmentioning

confidence: 99%

“…5 The BBB is a dynamic and complex interface between the blood and the central nervous system, having a key role in brain homeostasis and protection. 6 Although cerebral endothelium disturbance is commonly observed in the central nervous system (CNS) pathologies, 7 neither its cause nor the effective participation of BBB in such diseases is well established. Thus, given that BBB damage is an early event in many neurologic conditions, it is not surprising the growing interest in this barrier as a therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

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The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Coelho-Santos

Leitão

Cardoso

et al. 2015

J Cereb Blood Flow Metab

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Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Coelho-Santos

Leitão

Cardoso

et al. 2015

J Cereb Blood Flow Metab

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show abstract

“…Furthermore, LPS-activated microglia in vitro also showed no expression of AQP4 (data not shown). Another factor involved in neuroinflammation is the integrity of the bloodbrain barrier [26][27][28] . The hyperpermeability of the blood-brain barrier in AQP4 KO mice [29] could facilitate the entry of immune cells into the central nervous system during systemic LPS exposure.…”

Section: Discussionmentioning

confidence: 99%

Aquaporin-4 Mediates the Suppressive Effect of Lipopolysaccharide on Hippocampal Neurogenesis

Liang

Yong

Huang

et al. 2016

Neuroimmunomodulation

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Objective: Aquaporin-4 (AQP4), a key molecule for water homeostasis in the brain, is associated with adult neurogenesis, but its mechanisms regulating adult neural stem cells (aNSC) remain largely unexplored. Neuroinflammation has a relevant influence on adult neurogenesis, which is a common feature in various neurodegenerative diseases. Considering the possible link between neuroinflammation and AQP4, we speculate that AQP4 may mediate the synthesis and release of proinflammatory cytokines in glia and then indirectly regulate adult hippocampal neurogenesis. Methods: Using AQP4 knockout mice, we investigated the effects of AQP4 on hippocampal neurogenesis after lipopolysaccharide (LPS)-induced neuroinflammation. Results: We unexpectedly found that AQP4 deficiency attenuated the decrease in aNSC proliferation after systemic LPS exposure, accompanied by inhibition of glial activation and suppression of the production of proinflammatory cytokines in the hippocampus. Meanwhile, in vivo studies demonstrated that LPS-induced activated microglia did not express AQP4, indicating the impossibility of direct regulation of AQP4 to activate microglia. Furthermore, we demonstrated in vitro that AQP4 deficiency inhibited astrocyte activation and reduced the release of proinflammatory cytokines from astrocytes. Conclusion: Our data suggest that AQP4 mediates the suppressive effect of neuroinflammation on hippocampal neurogenesis via regulation of the astroglial response.

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“…Monocyte trafficking to the brain is usually observed in association with substantial CNS-related tissue pathology and inflammation, e.g., multiple sclerosis, traumatic injury, stroke, Alzheimer’s disease, or infection (Hafler et al, 2005; Gate et al, 2010; Donnelly et al, 2011; Hawthorne & Popovich, 2011; McGavern & Kang, 2011; de Vries et al, 2012). Therefore, the possibility that RSD could induce monocyte trafficking to the brain was intriguing because it would occur in the absence of CNS tissue pathology (Wohleb et al, 2013).…”

Section: Rsd-induced Behavioral and Cns Effectsmentioning

confidence: 99%

Peripheral and central effects of repeated social defeat stress: Monocyte trafficking, microglial activation, and anxiety

et al. 2015

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The development and exacerbation of depression and anxiety are associated with exposure to repeated psychosocial stress. Stress is known to affect the bidirectional communication between the nervous and immune systems leading to elevated levels of stress mediators including glucocorticoids (GCs) and catecholamines and increased trafficking of proinflammatory immune cells. Animal models, like the repeated social defeat (RSD) paradigm, were developed to explore this connection between stress and affective disorders. RSD induces activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary (HPA) axis activation, increases bone marrow production and egress of primed, GC-insensitive monocytes, and stimulates the trafficking of these cells to tissues including the spleen, lung, and brain. Recently, the observation that these monocytes have the ability to traffic to the brain perivascular spaces and parenchyma have provided mechanisms by which these peripheral cells may contribute to the prolonged anxiety-like behavior associated with RSD. The data that have been amassed from the RSD paradigm and others recapitulate many of the behavioral and immunological phenotypes associated with human anxiety disorders and may serve to elucidate potential avenues of treatment for these disorders. Here, we will discuss novel and key data that will present an overview of the neuroendocrine, immunological and behavioral responses to social stressors.

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Inflammatory events at blood–brain barrier in neuroinflammatory and neurodegenerative disorders: Implications for clinical disease

Cited by 100 publications

References 92 publications

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Aquaporin-4 Mediates the Suppressive Effect of Lipopolysaccharide on Hippocampal Neurogenesis

Peripheral and central effects of repeated social defeat stress: Monocyte trafficking, microglial activation, and anxiety

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