Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

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Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

Science Signaling ◽

10.1126/scisignal.aay5686 ◽

2020 ◽

Vol 13 (626) ◽

pp. eaay5686 ◽

Cited By ~ 4

Author(s):

Feifei Ma ◽

Ping Sun ◽

Xuejing Zhang ◽

Milton H. Hamblin ◽

Ke-Jie Yin

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Neuronal Loss ◽

Glucose Deprivation ◽

Brain Barrier ◽

Protein Abundance ◽

Barrier Dysfunction ◽

Small Noncoding Rnas ◽

Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

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Ιmmunity, Vascular Aging, and Stroke

Current Medicinal Chemistry ◽

10.2174/0929867329666220103101700 ◽

2022 ◽

Vol 29 ◽

Author(s):

Anna-Maria Louka ◽

Dimitrios Sagris ◽

George Ntaios

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Brain Barrier ◽

Low Grade ◽

Vascular Aging ◽

Barrier Dysfunction ◽

Blood Brain

Abstract: Stroke is one of the most devastating manifestations of cardiovascular disease. Growing age, arterial hypertension, and atherosclerosis are identified as independent risk factors for stroke, primarily due to structural and functional alterations in the cerebrovascular tree. Recent data from in vitro and clinical studies have suggested that the immune system influences atherosclerosis, promoting vascular stiffness and vascular aging and contributing to ischemic stroke, intracranial haemorrhage and microbleeds, white matter disease, and cognitive decline. Furthermore, aging is related to a chronic low-grade inflammatory state, in which macrophage, neutrophils, natural killer (NK cells), and B and T lymphocytes act as major effectors of the immune-mediated cell responses. Moreover, oxidative stress and vascular inflammation are correlated with endothelial dysfunction, vascular aging, blood-brain barrier disruption, lacunar lesions, and neurodegenerative disorders. This review discusses the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including the complex interplay between them and innate immunity, as well as vascular dysfunction, arterial stiffness, atherosclerosis, atherothrombosis, systemic inflammation, and blood-brain barrier dysfunction.

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Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

AJP Cell Physiology ◽

10.1152/ajpcell.00371.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. C1513-C1522 ◽

Cited By ~ 32

Author(s):

Robert R. Rigor ◽

Richard S. Beard ◽

Olesya P. Litovka ◽

Sarah Y. Yuan

Keyword(s):

Human Brain ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Brain Barrier ◽

Brain Diseases ◽

Barrier Dysfunction ◽

Microvascular Endothelium ◽

Blood Brain ◽

Pkc Isoforms ◽

Junction Protein

Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1β is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1β exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1β triggered activation of novel PKC isoforms δ, μ, and θ, followed by decreased transendothelial electrical resistance (TER). The IL-1β-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-θ or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-θ. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1β treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC-θ-dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1β is a central inflammatory mediator, our interpretation is that inhibition of PKC-θ or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.

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