Faculty Opinions recommendation of Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood-brain barrier.

Neisseria meningitidis is a commensal bacterium of the human nasopharynx. Occasionally, this bacterium reaches the bloodstream and causes meningitis after crossing the blood–brain barrier by an unknown mechanism. An immunohistological study of a meningococcal sepsis case revealed that neisserial adhesion was restricted to capillaries located in low blood flow regions in the infected organs. This study led to the hypothesis that drag forces encountered by the meningococcus in the bloodstream determine its attachment site in vessels. We therefore investigated the ability of N. meningitidis to bind to endothelial cells in the presence of liquid flow mimicking the bloodstream with a laminar flow chamber. Strikingly, average blood flows reported for various organs strongly inhibited initial adhesion. As cerebral microcirculation is known to be highly heterogeneous, cerebral blood velocity was investigated at the level of individual vessels using intravital imaging of rat brain. In agreement with the histological study, shear stress levels compatible with meningococcal adhesion were only observed in capillaries, which exhibited transient reductions in flow. The flow chamber assay revealed that, after initial attachment, bacteria resisted high blood velocities and even multiplied, forming microcolonies resembling those observed in the septicemia case. These results argue that the combined mechanical properties of neisserial adhesion and blood microcirculation target meningococci to transiently underperfused cerebral capillaries and thus determine disease development.

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Interaction mechanisms of encapsulated meningococci with eucaryotic cells: what does this tell us about the crossing of the blood–brain barrier by Neisseria meningitidis?

Current Opinion in Microbiology ◽

10.1016/s1369-5274(99)80012-5 ◽

1999 ◽

Vol 2 (1) ◽

pp. 71-77 ◽

Cited By ~ 30

Author(s):

Xavier Nassif

Keyword(s):

Neisseria Meningitidis ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Interaction Mechanisms ◽

Blood Brain

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CD44 regulates blood-brain barrier integrity in response to fluid shear stress

10.1101/2020.01.28.924043 ◽

2020 ◽

Author(s):

Brandon J. DeOre ◽

Paul P. Partyka ◽

Fan Fan ◽

Peter A. Galie

Keyword(s):

Blood Flow ◽

Shear Stress ◽

Blood Brain Barrier ◽

Fluid Shear Stress ◽

Small Gtpase ◽

Brain Barrier ◽

Fluid Shear ◽

Blood Brain

AbstractFluid shear stress is an important mediator of vascular permeability, yet the molecular mechanisms underlying the response of the blood-brain barrier to shear have yet to be studied in cerebral vasculature despite its importance for brain homeostasis. The goal of this study is to probe components of shear mechanotransduction within the blood-brain barrier to gain a better understanding of pathologies associated with changes in cerebral blood flow including ischemic stroke. Interrogating the effects of shear stress in vivo is complicated by the complexity of factors in the brain parenchyma and the difficulty associated with modulating blood flow regimes. Recent advances in the ability to mimic the in vivo microenvironment using three-dimensional in vitro models provide a controlled setting to study the response of the blood-brain barrier to shear stress. The in vitro model used in this study is compatible with real-time measurement of barrier function using transendothelial electrical resistance as well as immunocytochemistry and dextran permeability assays. These experiments reveal that there is a threshold level of shear stress required for barrier formation and that the composition of the extracellular matrix, specifically the presence of hyaluronan, dictates the flow response. Gene editing to modulate the expression of CD44, a receptor for hyaluronan that previous studies have identified to be mechanosensitive, demonstrates that the receptor is required for the endothelial response to shear stress. Manipulation of small GTPase activity reveals CD44 activates Rac1 while inhibiting RhoA activation. Additionally, adducin-γ localizes to tight junctions in response to shear stress and RhoA inhibition and is required to maintain the barrier. This study identifies specific components of the mechanosensing complex associated with the blood-brain barrier response to fluid shear stress, and therefore illuminates potential targets for barrier manipulation in vivo.

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Neisseria Meningitidis Opca Protein/MnO 2 Hybrid Nanoparticles for Overcoming Blood Brain Barrier to Treat Glioblastoma

Advanced Materials ◽

10.1002/adma.202109213 ◽

2022 ◽

pp. 2109213

Author(s):

Cheng‐Yuan Dong ◽

Qian‐Xiao Huang ◽

Han Cheng ◽

Di‐Wei Zheng ◽

Sheng Hong ◽

...

Keyword(s):

Neisseria Meningitidis ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Hybrid Nanoparticles ◽

Blood Brain

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Effects of transient loss of shear stress on blood–brain barrier endothelium: role of nitric oxide and IL-6

Brain Research ◽

10.1016/s0006-8993(03)02689-1 ◽

2003 ◽

Vol 977 (2) ◽

pp. 239-246 ◽

Cited By ~ 53

Author(s):

Ljiljana Krizanac-Bengez ◽

Miranda Kapural ◽

Fiona Parkinson ◽

Luca Cucullo ◽

Mohammed Hossain ◽

...

Keyword(s):

Nitric Oxide ◽

Shear Stress ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Blood Brain ◽

Transient Loss

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Numerical approach-based simulation to predict cerebrovascular shear stress in a blood-brain barrier organ-on-a-chip

Biosensors and Bioelectronics ◽

10.1016/j.bios.2021.113197 ◽

2021 ◽

pp. 113197

Author(s):

Sehoon Jeong ◽

Jae-Hyeong Seo ◽

Kunal Sandip Garud ◽

Sung Woo Park ◽

Moo-Yeon Lee

Keyword(s):

Shear Stress ◽

Blood Brain Barrier ◽

Numerical Approach ◽

Brain Barrier ◽

Blood Brain ◽

Organ On A Chip

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Rac1/Wave2/Arp3 Pathway Mediates Rat Blood-Brain Barrier Dysfunction under Simulated Microgravity Based on Proteomics Strategy

International Journal of Molecular Sciences ◽

10.3390/ijms22105165 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5165

Author(s):

Ranran Yan ◽

Huayan Liu ◽

Fang Lv ◽

Yulin Deng ◽

Yujuan Li

Keyword(s):

Oxidative Stress ◽

Blood Brain Barrier ◽

Proinflammatory Cytokine ◽

Brain Barrier ◽

Cell Junction ◽

Cycle Phase ◽

Blood Brain ◽

Proteomic Approach ◽

Cytokine Levels ◽

Stress Levels

The blood-brain barrier (BBB) is critical to maintaining central nervous system (CNS) homeostasis. However, the effects of microgravity (MG) on the BBB remain unclear. This study aimed to investigate the influence of simulated MG (SMG) on the BBB and explore its potential mechanism using a proteomic approach. Rats were tail-suspended to simulate MG for 21 days. SMG could disrupt the BBB, including increased oxidative stress levels, proinflammatory cytokine levels, and permeability, damaged BBB ultrastructure, and downregulated tight junctions (TJs) and adherens junctions (AJs) protein expression in the rat brain. A total of 554 differentially expressed proteins (DEPs) induced by SMG were determined based on the label-free quantitative proteomic strategy. The bioinformatics analysis suggested that DEPs were mainly enriched in regulating the cell–cell junction and cell–extracellular matrix biological pathways. The inhibited Ras-related C3 botulinum toxin substrate 1 (Rac1)/Wiskott–Aldrich syndrome protein family verprolin-homologous protein 2 (Wave2)/actin-related protein 3 (Arp3) pathway and the decreased ratio of filamentous actin (F-actin) to globular actin contributed to BBB dysfunction induced by SMG. In the human brain microvascular endothelial cell (HBMECs), SMG increased the oxidative stress levels and proinflammatory cytokine levels, promoted apoptosis, and arrested the cell cycle phase. Expression of TJs and AJs proteins were downregulated and the distribution of F-actin was altered in SMG-treated HBMECs. The key role of the Rac1/Wave2/Arp3 pathway in BBB dysfunction was confirmed in HBMECs with a specific Rac1 agonist. This study demonstrated that SMG induced BBB dysfunction and revealed that Rac1/Wave2/Arp3 could be a potential signaling pathway responsible for BBB disruption under SMG. These results might shed a novel light on maintaining astronaut CNS homeostasis during space travel.

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