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Cited by 573Barrier Structure and Function StudiesNeuroinflammation and Neurodegeneration MechanismsExtracellular vesicles in disease

The impact of microglial activation on blood-brain barrier in brain diseases

Open access
da Fonseca, Anna Carolina Carvalho, Matias, Diana, Garcia, Celina, Amaral, Rackele, Geraldo, Luiz Henrique, Freitas, Catarina, Lima, Flavia Regina Souza·2014·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2014.00362PMC PMC4217497
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Abstract

The blood-brain barrier (BBB), constituted by an extensive network of endothelial cells (ECs) together with neurons and glial cells, including microglia, forms the neurovascular unit (NVU). The crosstalk between these cells guarantees a proper environment for brain function. In this context, changes in the endothelium-microglia interactions are associated with a variety of inflammation-related diseases in brain, where BBB permeability is compromised. Increasing evidences indicate that activated microglia modulate expression of tight junctions, which are essential for BBB integrity and function. On the other hand, the endothelium can regulate the state of microglial activation. Here, we review recent advances that provide insights into interactions between the microglia and the vascular system in brain diseases such as infectious/inflammatory diseases, epilepsy, ischemic stroke and neurodegenerative disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review synthesizes evidence that activated microglia impair blood-brain barrier (BBB) function through release of inflammatory mediators (ROS, TNF-α, IL-1β, IL-6, MMPs, chemokines), while the endothelium can in turn regulate microglial activation. It argues that microglia–endothelium crosstalk within the neurovascular unit is a central, and potentially targetable, mechanism in epilepsy, ischemic stroke, infectious/inflammatory disease, Alzheimer's disease and multiple sclerosis.

Key findings

  • In rat brain microvascular endothelial cell (RBEC)/microglia co-culture, abluminal LPS did not change transendothelial electrical resistance (TEER) in RBEC monolayers alone, but decreased TEER and increased sodium-fluorescein permeability in co-culture, in a manner dependent on microglial cell number; the disrupted ZO-1, claudin-5 and occludin staining was restored by the NADPH oxidase inhibitor DPI (Sumi et al., 2010).
  • In mouse brain capillary endothelial (MBEC4)/microglia co-culture, LPS-activated microglia increased Na-F permeability, an effect blocked by a neutralizing antibody against TNF-α (Nishioku et al., 2010).
  • In CD200-deficient mice, increased BBB permeability was associated with T cell/macrophage entry, elevated IFNγ, and increased TNF-α, promoting classical microglial activation (Denieffe et al., 2013).
  • In rat hippocampus, Aβ1–42 injection caused time-dependent increases in fibrinogen and microgliosis and significantly increased IgG immunoreactivity; anti-Mac-1 reduced IgG, consistent with reduced microglial reactivity and greater BBB preservation (Ryu and McLarnon, 2009).
  • In stroke, BBB disruption is described as biphasic: an early opening (12–48 h) driven mainly by ROS activating latent MMP-2, and a delayed secondary opening (48–72 h) driven by sustained inflammation and microglial MMP-2/3/9 production; activated microglia were reported up to 16 weeks after 2-hour MCAO in rats (Ekdahl et al., 2009), while neutrophil infiltration was more prominent only with longer MCAO periods and few exogenous macrophages infiltrated over the first 72 h (Denes et al., 2007).
  • Minocycline, a microglial inhibitor, preserved BBB constituents in vitro and reduced BBB disruption and hemorrhage in vivo (Yenari et al., 2006), and in two clinical trials in ischemic stroke patients improved neurological functional outcome, alone and combined with fibrinolysis (Fagan et al., 2011).

Methods

  • Design: narrative literature review of "recent advances" on microglia–vascular interactions in brain disease; no systematic search strategy, inclusion criteria, or quantitative synthesis is reported.
  • Scope: developmental microglia–endothelium interaction, mechanisms of microglial activation and BBB impairment, and disease-specific sections on epilepsy, stroke, Alzheimer's disease and multiple sclerosis.
  • Evidence base: cited in vitro co-culture systems (RBEC/microglia, MBEC4/microglia), rodent models (PU.1-deficient mice, clodronate liposome depletion, choroidal neovascularization, Aβ1–42 intra-hippocampal injection, tMCAO, EAE, TMEV-IDD, CD200-deficient mice), human AD and MS tissue, and clinical trial reports; the review also presents one original confocal image (Figure 1) of IBA1-positive microglia and IsolectinB4-positive endothelium in a 1-month-old mouse cortex.

Limitations

  • The paper states no explicit limitations section; it acknowledges that "the mechanisms involved in the multifaceted interactions between the constituents of the NVU are not yet fully uncovered," particularly how microglial activation drives BBB disruption.
  • Evident from the text: as a narrative review it relies on heterogeneous cited studies (in vitro co-cultures, animal models, human tissue, clinical trials) without systematic appraisal, and several mechanistic claims are hedged by the authors as hypotheses or suggestions (e.g., "we can hypothesize," "we suggest") rather than demonstrated findings.
  • Evident from the text: much of the mechanistic evidence is preclinical (rodent and cell-culture), and the authors note uncertainty about the relative contribution of resident microglia versus infiltrating bone-marrow-derived myeloid cells in inflammatory conditions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fncel.2014.00362

Cites

191 of 191 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 129 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Resident microglia associate with endothelium in the cortical microvascular bed.

    “Representative confocal image revealing close interaction between microglia (IBA1, green) and endothelial cells (IsolectinB4, red) in a 50 micron-cryopreserved cross-section of a 1 month-old mouse cortex.”
    Quote in the paperSubstantial claim
  • Interpretationcitation

    Microglia certainly play an important role in inflammatory pathologies of the CNS.

    “but undoubtedly microglia certainly play an important role in these pathologies (Perry et al., 2010; Graeber et al., 2011).”
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    • cites Perry et al., 2010 source

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    • cites Graeber et al., 2011 source

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  • Interpretationcitation

    Microglial activation impairs BBB function by the release of various molecules leading to a hyperpermeability condition associated with inflammation similar to what occurs in certain neurodegenerative disorders, including AD and MS.

    “Considering all the studies mentioned above, microglial activation impairs BBB function by the release of various molecules leading to a hyperpermeability condition associated with inflammation that is similar to what occurs in certain neurodegenerative disorders, including AD and Multiple Sclerosis (MS).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Perry et al., 2010 source

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    • cites Graeber et al., 2011 source

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    • Rests on an assumption: The findings from animal models and in vitro co-culture systems about microglia-endothelium interactions are representative of human brain diseases.
  • Premisecitation

    TNF-α released from activated microglia contributes to BBB dysfunction.

    “indicating that TNF-α contributes to BBB dysfunction (Nishioku et al., 2010).”
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    • cites Nishioku et al., 2010 source

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  • Interpretationcitation

    Inflammatory pathways activated by microglial cells induce BBB dysfunction, which contributes to epileptogenesis.

    “These current findings show the increasing importance of the inflammatory pathways activated by microglial cells in inducing BBB dysfunction, which contributes to epileptogenesis.”
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    • cites Vezzani et al., 2011 source

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  • Classified as probably not a substantial claim. 4
  • May combine two claims. 37

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The endothelium can regulate the state of microglial activation.

    “On the other hand, the endothelium can regulate the state of microglial activation.”
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    Premisecitation

    Neuroinflammation is a key component of cell death cascades in stroke, with microglial cells and peripheral leukocytes, especially neutrophils and monocytes/macrophages, as main players.

    “One of the key components of the cell death cascades in stroke is neuroinflammation, where the main players are microglial cells and the peripheral leukocytes, especially neutrophils and monocytes/macrophages.”
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    Premisecitation

    Microglial and astrocytic IL-1β act directly on the endothelium, altering BBB permeability and contributing to epileptogenesis.

    “Microglial and astrocytic IL-1β act directly on the endothelium, altering BBB permeability and contributing to epileptogenesis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ravizza et al., 2008a,b

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    • cites Morin-Brureau et al., 2011 source

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    • cites Librizzi et al., 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia play a role in CNS angiogenesis by serving as a bridge to promote tip cell fusion, vascular plexus growth following sprouting induction and tip cell migration by VEGF.

    “the authors suggest that microglia play a role in CNS angiogenesis by serving as a bridge to promote tip cell fusion, vascular plexus growth following sprouting induction and tip cell migration by VEGF (Fantin et al., 2010).”
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    Interpretationcitation

    Microglia are present in the embryonic CNS territory prior to endothelial invasion and participate in cerebrovasculature growth, placing microglia-endothelium interactions as a possible key mechanism in BBB formation and regulation.

    “The fact that microglia are present in the embryonic CNS territory prior to endothelial invasion and that they participate in cerebrovasculature growth place the interactions between microglia and CNS endothelium as a possible key mechanism in BBB formation and regulation.”
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    • cites Cuadros et al., 1993 source

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    Premisecitation

    Microglia become activated under brain injury and immunological stimuli and undergo alterations from a resting state to an active state.

    “Microglia become activated under brain injury and immunological stimuli (Kreutzberg, 1996) and undergo several alterations from a “resting state” to an active state (Hanisch and Kettenmann, 2007; Kettenmann et al., 2011).”
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    Premisecitation

    In the delayed phase, microglial ROS, especially superoxide radical O2−, increase vascular permeability by stimulating MMP-2/MMP-3/MMP-9 production by microglia, astrocytes and endothelial cells, contributing to hemorrhagic transformation and vasogenic edema.

    “In this phase, MMPs are important mediators: microglial ROS, especially superoxide radical O2−, increase vascular permeability also by stimulating MMP-2/MMP-3/MMP-9 production by microglia, astrocytes and ECs (Gottschall and Deb, 1996; Asahi et al., 2001; Rosenberg et al., 2001), contributing to hemorrhagic transformation and vasogenic edema.”
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    • cites Gottschall and Deb, 1996

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    • cites Asahi et al., 2001 source

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    • cites Rosenberg et al., 2001 source

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    Premisecitation

    After ischemic insult, recruitment of immune cells occurs in a biphasic dynamics: in the acute phase (within minutes), microglial cells are rapidly recruited to the injury site due to immediate release of cytokines and chemokines.

    “After the ischemic insult, the recruitment of immune cells occurs in a biphasic dynamics. In the acute phase (within minutes), microglial cells are rapidly recruited to the injury site, due to the immediate release of cytokines and chemokines.”
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    • cites Kunsch and Medford, 1999

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    • cites Jin et al., 2010 source

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    Premisecitation

    Blood-derived macrophages and microglia have many functions in the dynamic process of CNS injury and repair, affecting BBB permeabilization, which in turn can aggravate stroke.

    “Blood-derived macrophages and microglia appear to have many functions in the dynamic process of CNS injury and repair, affecting BBB permeabilization, which in turn can aggravate stroke (Hallenbeck, 2002; Sandoval and Witt, 2008; Jiao et al., 2011).”
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    • cites Sandoval and Witt, 2008

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    • cites Jiao et al., 2011 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IGF-1 promotes neuroprotection and neuroregeneration.

    “Some in vitro and in vivo studies have shown the role of IGF-1 in promoting neuroprotection and neuroregeneration (Li et al., 2010; Selvamani et al., 2012; Sohrabji and Williams, 2013; Bake et al., 2014).”
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    • cites Li et al., 2010

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    • cites Sohrabji and Williams, 2013

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    Premisecitation

    ROS and NO can reorganize the cytoskeleton of endothelial cells and modulate tight junction proteins claudin-5 and occludin.

    “In addition, ROS and NO can also reorganize the cytoskeleton of ECs and modulate tight junction proteins claudin-5 and occludin (Yamagata et al., 2004; Schreibelt et al., 2007) activate microglial cells; and up-regulate inflammatory mediators in the first 48 h.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Yamagata et al., 2004 source

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    • cites Schreibelt et al., 2007 source

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    Premisecitation

    These actions enhance influx of peripheral leukocytes and contribute to formation of vasogenic edema by allowing diffusion of sodium and water.

    “These actions not only help enhancing the influx of peripheral leukocytes, but also contribute to the formation of vasogenic edema by allowing the diffusion of sodium and water (Sandoval and Witt, 2008).”
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    • cites Sandoval and Witt, 2008

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    Premisecitation

    The neuroinflammatory state activates the JNK pathway in microglia and endothelial cells, leading to microglial and endothelial activation with direct and microglial-induced BBB disruption, further cytokine production and perpetuation of the neuroinflammatory process.

    “Recently, the neuroinflammatory state was shown to activate the c-Jun N-terminal kinase (JNK) pathway not only in microglia but also in ECs, leading to microglial and endothelial activation with direct and microglial-induced BBB disruption, further cytokine production and perpetuation of the neuroinflammatory process (Tu et al., 2011; Wang et al., 2012).”
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    • cites Tu et al., 2011

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    Premisecitation

    ROS activate latent MMP-2 minutes after ischemic insult and are produced by microglia and astrocytes through the HIF-1α pathway.

    “They activate the latent MMP-2 min after the ischemic insult, and are produced by microglia and astrocytes through the HIF-1α pathway (Yang and Rosenberg, 2011; Obermeier et al., 2013).”
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    • cites Yang and Rosenberg, 2011

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    • cites Obermeier et al., 2013 source

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    Premisecitation

    Minocycline inhibits activation of microglia and brain infiltrating blood-derived macrophages and protects cultured neurons from excitotoxic insults by preventing microglial generation of glutamate, IL-1β and NO.

    “minocycline, a member of the tetracycline antibiotic family, inhibits activation of microglia and brain infiltrating blood-derived macrophages and protects cultured neurons from excitotoxic insults by preventing microglial generation of glutamate, IL-1β and NO (Yrjänheikki et al., 1998, 1999; Tikka et al., 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Yrjänheikki et al., 1998, 1999

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    • cites Tikka et al., 2001 source

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  • May combine two claims.

    Interpretationcitation

    Inhibiting microglial activation may limit BBB disruption and reduce vasogenic edema in ischemic stroke, reducing ischemic tissue volume and neuronal deficits, and preventing hemorrhagic transformation.

    “Inhibiting microglial activation may limit BBB disruption and reduce vasogenic edema in the context of ischemic stroke, reducing the volume of ischemic tissue and neuronal deficits, as well as preventing hemorrhagic transformation (Tikka et al., 2001; Yenari et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Tikka et al., 2001 source

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    • cites Yenari et al., 2006 source

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  • May combine two claims.

    Interpretationreasoning

    These mediators also indirectly lead to BBB damage by acting on different components of the NVU: activating MMPs and acting on astrocytes and pericytes through ROS, NO and cytokines.

    “These mediators also indirectly lead to BBB damage, by acting not on ECs, but on different components of the NVU: activating MMPs and acting on astrocytes and pericytes through ROS, NO and cytokines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ROS and NO activate microglial cells and up-regulate inflammatory mediators in the first 48 h.

    “In addition, ROS and NO can also reorganize the cytoskeleton of ECs and modulate tight junction proteins claudin-5 and occludin (Yamagata et al., 2004; Schreibelt et al., 2007) activate microglial cells; and up-regulate inflammatory mediators in the first 48 h.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yamagata et al., 2004 source

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    • cites Schreibelt et al., 2007 source

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    Premisecitation

    In the acute phase, activated microglia enhance release of ROS (through NADPH oxidase and MPO), cytokines (IL-1β, IL-6, TNF-α) and chemokines (MCP-1, CXCL-1, MIP-1α).

    “These cells are activated, enhancing the release of ROS (through NADPH oxidase and MPO), cytokines (i.e., IL-1β, IL-6 and TNF-α) and chemokines (MCP-1, CXCL-1 and MIP-1α).”
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    • cites Kunsch and Medford, 1999

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    • cites Jin et al., 2010 source

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    • cites Enzmann et al., 2013 source

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    Premisecitation

    Over the first 72 h after tMCAo, few infiltrating exogenous macrophages are observed, while proliferating resident microglia increase profoundly.

    “Also, very few infiltrating exogenous macrophages were observed over the first 72 h period and, instead, a profound increase in proliferating resident microglia cells was observed (Denes et al., 2007).”
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    • cites Denes et al., 2007 source

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    Interpretationreasoning

    Microglia have a role in endothelial cell damage and BBB disruption in stroke, making these cells a possible target to minimize ischemic damage in stroke patients.

    “All these data suggest that microglia has a role in the EC damage and BBB disruption in stroke, making these cells a possible target to minimize the ischemic damage in stroke patients.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microglial-induced late-phase BBB disruption is due to direct effects on endothelial cells: IL-1β and TNF-α downregulate tight junction protein expression in ECs, and together with IL-6 modulate expression of adhesion molecules ICAM-1 and VCAM.

    “Apart from the effects of MMPs, microglial-induced late-phase BBB disruption is due to direct effects on ECs: IL-1β and TNF-α downregulate tight junction proteins expression in ECs (Yamagata et al., 2004; Jiao et al., 2011) and, together with IL-6, modulate the expression of adhesion molecules (ICAM-1 and VCAM; Hallenbeck, 2002).”
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    • cites Yamagata et al., 2004 source

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    • cites Jiao et al., 2011 source

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    • cites Hallenbeck, 2002 source

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    Premisecitation

    MMPs are further stimulated by NK-κB and HIF-1α and disrupt tight junction proteins (ZO-1, claudin-5 and occludin), rendering the BBB leaky; these downstream effects are reverted by blocking NOS.

    “MMPs are further stimulated by NK-κB and HIF-1α and disrupt TJ proteins (as ZO-1, claudin-5 and occludin), rendering the BBB leaky, downstream effects which were shown to be reverted by blocking NOS (Yang and Rosenberg, 2011; Gu et al., 2012; Obermeier et al., 2013).”
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    • cites Yang and Rosenberg, 2011

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    • cites Obermeier et al., 2013 source

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    Premisecitation

    In AD, microglia and astrocytes can promote clearance of Aβ; if they are not able to do that, accumulation of Aβ deposits leads to neuronal death.

    “In AD, these cells can promote the clearance of Aβ, however, if they are not able to do that, there is an accumulation of Aβ deposits leading to neuronal death (Rogers et al., 2002).”
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    • cites Rogers et al., 2002 source

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    Interpretationreasoning

    When activated, microglia impair BBB function through release of several inflammatory modulators leading to a hyperpermeability condition, which is associated with several brain disorders.

    “When activated, microglia impair BBB function through the release of several inflammatory modulators leading to a hyperpermeability condition, which is associated with several brain disorders.”
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    Premisecitation

    MS is a chronic, progressive and neuroinflammatory demyelinating disease of the CNS, which involves an energy deficit, tissue remodeling, microglial activation and loss of BBB integrity.

    “Multiple sclerosis is a chronic, progressive and neuroinflammatory demyelinating disease of the CNS, which involves an energy deficit, tissue remodeling, microglial activation and loss of BBB integrity (Lassmann et al., 2012).”
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    • cites Lassmann et al., 2012 source

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    Premisecitation

    In AD brains, activated microglia and astrocytes are present around Aβ plaques, with release of inflammatory cytokines such as IL-1, IL-6, TNF-α and transforming growth factor-β.

    “it was observed in AD brains the presence of activated microglia and astrocytes around Aβ plaques, with the release of inflammatory cytokines, such as IL-1 and IL-6, TNF-α and transforming growth factor-β (TNF-β; Wyss-Coray, 2006; Zhou et al., 2012).”
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    • cites Wyss-Coray, 2006 source

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    • cites Zhou et al., 2012 source

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    Premisecitation

    Systemic inflammation contributes to MS disease progression and activation of immune cells allows infiltration of T and B cells into the CNS, promoting release of chemokines that stimulate migration of more immune cells, leading to BBB disruption.

    “Previous studies showed that systemic inflammation contributes to the disease progression and the activation of immune cells allows the infiltration of T and B cells into the CNS, promoting the release of chemokines that in turn stimulate the migration of more immune cells, leading to BBB disruption (Holman et al., 2011; Kooij et al., 2011; Larochelle et al., 2011; Willis, 2011).”
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    • cites Holman et al., 2011 source

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    • cites Larochelle et al., 2011 source

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    Premisecitation

    High levels of Aβ are correlated with production of CCL2 by microglia, which leads to BBB impairment.

    “Moreover, high levels of Aβ are correlated with production of CCL2 by microglia, which leads to BBB impairment (Roberts et al., 2012).”
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    • cites Roberts et al., 2012 source

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    Premisecitation

    There are two different types of inflammation in MS: the first is the initial response to the disease, involving infiltration of CD4+ and CD8+ T-cells and robust microglial activation; the second occurs due to myelin destruction, stimulating secondary recruitment of T cells, B cells and macrophages.

    “Hereupon, there are two different types of inflammation in MS. The first consists in the initial response to the disease, involving the infiltration of CD4+ and CD8+ T-cells and robust microglial activation; the second occurs due to the myelin destruction, stimulating the secondary recruitment of T cells, B cells and macrophages (Lassmann et al., 2012).”
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    Premisecitation

    Intracranial injection of thrombin activates microglia, leading to production of NO and TNFα via JAK2-STAT3 signaling pathway, which induce BBB disruption.

    “Furthermore, it was shown that intracranial injection of thrombin activates microglia, leading to the production of NO and TNFα via JAK2-STAT3 signaling pathway, which induce BBB disruption.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Huang et al., 2008a,b

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    Premisecitation

    Elimination of Aβ from the brain and consequent impairment of microglial activation decrease ROS, nitrogen compounds and inflammatory cytokines produced by microglial cells, which are correlated with activation of endothelial cells.

    “It has already been shown that the elimination of Aβ from the brain and the consequent impairment of microglial activation decrease ROS, nitrogen compounds and also inflammatory cytokines produced by microglial cells, which are correlated with the activation of ECs (Dickstein et al., 2006).”
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    • cites Dickstein et al., 2006 source

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    Premisecitation

    During inflammation and demyelination in MS, activation of microglial cells leads to release of cytotoxic factors such as NO and ROS, provoking myelin damage, release of proinflammatory cytokines (IFNγ, TNF-α and IL-1β), as well as chemokines (MCP-1), ultimately inducing BBB disruption.

    “Moreover, during inflammation and demyelination in MS, the activation of microglial cells lead to the release of cytotoxic factors, such as NO and ROS, provoking myelin damage, release of proinflammatory cytokines (IFNγ, TNF-α and IL-1β), as well as chemokines (MCP-1), ultimately inducing BBB disruption (Mahad and Ransohoff, 2003).”
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    • cites Mahad and Ransohoff, 2003

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Microglia activation plays an important role during BBB disruption in AD.

    “Thus, regarding all evidences described above, we can hypothesize that microglia activation plays an important role during BBB disruption, which substantiates the need to study other factors correlated with inflammatory pathways, as potential targets of new strategies to reduce microglial-dependent inflammation in the brain of AD patients.”
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    Premisecitation

    Inhibition of microglial activation by minocycline favors differentiation of oligodendrocyte precursors and immature oligodendrocytes, which are responsible for remyelination of neurons, an important event for improvement of MS condition.

    “The inhibition of microglial activation by minocycline favors the differentiation of oligodendrocyte precursors and immature oligodendrocytes. These cells are responsible for remyelination of neurons, an important event for improvement of MS condition (Li et al., 2005; Yenari et al., 2006; Defaux et al., 2011; Miron et al., 2013).”
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    Premisecitation

    Dipyridamole attenuates expression of Toll-like receptor stimulation-dependent cytokines and chemokines in human microglia, reduces microglial activity in EAE mice, and consequently decreases IL-1β, TNF-α and IL-6 expression, which are responsible for increased BBB permeability.

    “Recently published data demonstrated that dipyridamole attenuates the expression of Toll-like receptor stimulation-dependent cytokines and chemokines in human microglia, reduces microglial activity in EAE mice, and consequently decreases IL-1β, TNF-α and IL-6 expression, which are responsible for increased BBB permeability (Sloka et al., 2013).”
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    • cites Sloka et al., 2013 source

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    Premisecitation

    In EAE, activation of microglia precedes infiltration of peripheral macrophages and occurs before the onset of the disease.

    “experimental autoimmune encephalomyelitis (EAE), where activation of microglia precedes infiltration of peripheral macrophages and occurs before the onset of the disease (Sriram and Steiner, 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sriram and Steiner, 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated microglia express ROS-generating enzymes such as NADPH oxidase, which are responsible for degeneration of oligodendrocytes and increased BBB permeability by downregulating expression of VE-cadherin, occludin and claudin-5 proteins in microvascular endothelial cells.

    “Activated microglia are known to express ROS-generating enzymes, such as NADPH oxidase, which are responsible for degeneration of oligodendrocytes and increased BBB permeability by downregulating the expression of VE-cadherin, occludin and claudin-5 proteins in microvascular ECs (Fischer et al., 2012; Rochfort et al., 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fischer et al., 2012 source

      Not checked in the free run.

    • cites Rochfort et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibrinogen induces activation of microglia and consequently release of ROS, inducing axonal damage.

    “In this event, fibrinogen induces the activation of microglia and consequently the release of ROS, inducing axonal damage (Davalos et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Davalos et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LPS induces production of TNF-α in the brain by microglial cells, which promotes BBB dysfunction and also causes neuronal cell death by phagocytosis.

    “On the other hand, it has been shown that LPS induces the production of TNF-α in the brain by microglial cells, which promotes BBB dysfunction and also causes neuronal cell death by phagocytosis (Tanaka et al., 2006; Nishioku et al., 2010; Smith et al., 2012; Neniskyte et al., 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Tanaka et al., 2006 source

      Not checked in the free run.

    • cites Nishioku et al., 2010 source

      Not checked in the free run.

    • cites Smith et al., 2012 source

      Not checked in the free run.

40 of 40

  • The paper relies on this without support.

    The findings from animal models and in vitro co-culture systems about microglia-endothelium interactions are representative of human brain diseases.

    “Considering all the studies mentioned above, microglial activation impairs BBB function by the release of various molecules leading to a hyperpermeability condition associated with inflammation that is similar to what occurs in certain neurodegenerative disorders, including AD and Multiple Sclerosis (MS).”

  • The paper relies on this without support.

    Microglial activation is a common and comparable process across the different brain diseases discussed (infectious/inflammatory diseases, epilepsy, ischemic stroke and neurodegenerative disorders).

    “Taking all the recent data into consideration, we can suggest that the cells of the NVU, specially glial cells, have an overwhelming importance in epileptogenesis.”

  • The paper relies on this without support.

    BBB disruption worsens the clinical picture of stroke patients by causing intracerebral vasogenic edema and hemorrhagic transformation.

    “BBB disruption is another key event in the pathogenesis of stroke, as it can worsen the clinical picture of the patients by the formation of intracerebral vasogenic edema and hemorrhagic transformation.”

  • The paper relies on this without support.

    Findings from animal models of ischemic stroke, AD, and MS can be generalized to human patients.

    “In vivo models helped clarifying the kinetics of the immune cells in ischemic stroke”
    “Several studies using animal models have further contributed with in vivo evidences of the importance of microglia during AD progression.”

  • The paper relies on this without support.

    Pharmacological modulation of microglial activation will produce net clinical benefit in AD and MS despite microglia's beneficial roles.

    “Taking into account the literature reviewed about AD and MS, we suggest that pharmacological modulation of microglial activation may control the impairment of BBB in these diseases.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Minocycline's effect on remyelination conflicts with a cited reference

    Major

    The review presents microglial inhibition by minocycline as favoring cells responsible for remyelination and cites Li et al. (2005). The cited study's title instead says that minocycline-mediated inhibition impairs progenitor-cell responses and remyelination.

  • Transforming growth factor-β is given inconsistent abbreviations

    Minor

    The Alzheimer's disease section abbreviates transforming growth factor-β as TNF-β, whereas an earlier section calls it TGF-β.

  • Alzheimer's disease progression is described in opposite directions

    Minor

    The review says the deficient mouse model showed disease regression, but the title of its cited El Khoury study says Ccr2 deficiency accelerated progression of Alzheimer-like disease.

3 of 3

Cites

1 retracted

Flagged first, then by citations

1 of the 192 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S.
Affiliations
Universidade Federal do Rio de Janeiro (BR)
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2014-11-03
Volume
8
Pages
362-362
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2014.00362
PMC
PMC4217497
OpenAlex
W2051140555
Semantic Scholar
c5be3f0efc87bc47ecc037aeddfe23499572e499
Cited by
572
References
192
Citations by year
2026: 37 · 2025: 49 · 2024: 51 · 2023: 50 · 2022: 61 · 2021: 52 · 2020: 71 · 2019: 43 · 2018: 59 · 2017: 43 · 2016: 36 · 2015: 19 · 2014: 1
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
microglial activation, blood-brain barrier, neurovascular unit, endothelial cells, tight junctions, blood-brain barrier permeability, neuroinflammation, epilepsy, ischemic stroke, neurodegenerative diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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