Early BBB breakdown and subacute inflammasome activation and pyroptosis as a result of cerebral venous thrombosis

Rashad, Sherif; Niizuma, Kuniyasu; Sato-Maeda, Mika; Fujimura, Miki; Mansour, Ahmed; Endo, Hidenori; Ikawa, Shuntaro; Tominaga, Teiji

doi:10.1016/j.brainres.2018.06.029

Cited by 54 publications

(72 citation statements)

References 55 publications

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“…In addition, it was found that in ECs IL-18 increases the expression of matrix metalloproteinases (MMPs) [58], proteases that were found to degrade junctional proteins [59]. Infiltrating T lymphocytes appear to be the main source of MMP-2 and MMP-9, though brain ECs and pericytes also make an active contribution to MMP-9 production [60,61]. Notably, MMP-9 gene expression was not elevated in our in vivo experiment (Fig.…”

Section: Discussionmentioning

confidence: 67%

Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair

Israelov

Ravid

Atrakchi

et al. 2020

J Neuroinflammation

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Background Excessive inflammation might activate and injure the blood-brain barrier (BBB), a common feature of many central nervous system (CNS) disorders. We previously developed an in vitro BBB injury model in which the organophosphate paraoxon (PX) affects the BBB endothelium by attenuating junctional protein expression leading to weakened barrier integrity. The objective of this study was to investigate the inflammatory cellular response at the BBB to elucidate critical pathways that might lead to effective treatment in CNS pathologies in which the BBB is compromised. We hypothesized that caspase-1, a core component of the inflammasome complex, might have important role in BBB function since accumulating evidence indicates its involvement in brain inflammation and pathophysiology. Methods An in vitro human BBB model was employed to investigate BBB functions related to inflammation, primarily adhesion and transmigration of peripheral blood mononuclear cells (PBMCs). Caspase-1 pathway was studied by measurements of its activation state and its role in PBMCs adhesion, transmigration, and BBB permeability were investigated using the specific caspase-1 inhibitor, VX-765. Expression level of adhesion and junctional molecules and the secretion of pro-inflammatory cytokines were measured in vitro and in vivo at the BBB endothelium after exposure to PX. The potential repair effect of blocking caspase-1 and downstream molecules was evaluated by immunocytochemistry, ELISA, and Nanostring technology. Results PX affected the BBB in vitro by elevating the expression of the adhesion molecules E-selectin and ICAM-1 leading to increased adhesion of PBMCs to endothelial monolayer, followed by elevated transendothelial-migration which was ICAM-1 and LFA-1 dependent. Blocking caspase-8 and 9 rescued the viability of the endothelial cells but not the elevated transmigration of PBMCs. Inhibition of caspase-1, on the other hand, robustly restored all of barrier insults tested including PBMCs adhesion and transmigration, permeability, and VE-cadherin protein levels. The in vitro inflammatory response induced by PX and the role of caspase-1 in BBB injury were corroborated in vivo in isolated blood vessels from hippocampi of mice exposed to PX and treated with VX-765. Conclusions These results shed light on the important role of caspase-1 in BBB insult in general and specifically in the inflamed endothelium, and suggest therapeutic potential for various CNS disorders, by targeting caspase-1 in the injured BBB.

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Section: Discussionmentioning

confidence: 67%

Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair

Israelov

Ravid

Atrakchi

et al. 2020

J Neuroinflammation

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“…During sepsis, multiple complement proteins may enter the CNS and engage in neuroinflammation (45). It was not until 12 h after SE infection that plasma complement factors (e.g., C1QA, C1R, and C5) changed in concentration and other complement factors (C2, C4BPA, C5, and C8B) were affected at 24 h. The small activation fragments affected by SE infection, such as C3, C4a, and C5a, increase the permeability of blood vessels and attract leukocytes (8, 20, 21). The complement system also plays a role in eliminating invading bacteria and regulating the immune response to CNS infection by another Gram-positive bacteria, Streptococcus pneumonia (46).…”

Section: Discussionmentioning

confidence: 99%

“…CSF proteins were profiled to reveal changes pertaining to neuroinflammation in the surrounding CNS. The potential inflammatory effect of selected brain proteins, including NPY, a neuroimmune messenger (14–16) and memory and learning regulator (16, 17), and IL-18, a pro-inflammatory cytokine related to inflammation and blood–CSF barrier integrity (18–20), were further investigated using in vitro cell culture systems.…”

Section: Introductionmentioning

confidence: 99%

Rapid Proteome Changes in Plasma and Cerebrospinal Fluid Following Bacterial Infection in Preterm Newborn Pigs

et al. 2019

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Background: Neonatal infection and sepsis are common for preterm infants due to their immature immune system. Early diagnosis is important for effective treatment, but few early markers of systemic and neuro-inflammatory responses in neonates are known. We hypothesised that systemic infection with Staphylococcus epidermidis (SE), a Gram-positive bacteria, induces acute changes to proteins in the plasma and cerebrospinal fluid (CSF), potentially affecting the immature brain of preterm neonates.Methods: Using preterm pigs as a model for preterm infants, plasma and CSF samples were collected up to 24 h after SE infection and investigated by untargeted mass spectrometry (MS)-based proteomics. Multiple differentially expressed proteins were further studied in vitro.Results: The clinical signs of sepsis and neuroinflammation in SE-infected piglets were associated with changes of multiple CSF and plasma proteins. Eight plasma proteins, including APOA4, haptoglobin, MBL1, vWF, LBP, and sCD14, were affected 6 h after infection. Acute phase reactants, including complement components, showed a time-dependent activation pattern after infection. Feeding bovine colostrum reduced the sepsis-related changes in clinical indices and plasma proteins. Neuroinflammation-related neuropeptide Y (NPY), IL-18, and MMP-14 showed distinct changes in the CSF and several brain regions (the prefrontal cortex, PVWM, and hippocampus) 24 h after infection. These changes were verified in TLR2 agonist-challenged primary microglia cells, where exogenous NPY suppressed the inflammatory response.Conclusion: Systemic infection with SE induces inflammation with rapid proteome changes in the plasma and CSF in preterm newborn pigs. The observed early markers of sepsis and neuroinflammation in preterm pigs may serve as novel biomarkers for sepsis in preterm infants.

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“…Western blotting was performed as previously described 32 . Briefly, cells were collected and lysed in NE-PER nuclear and cytoplasmic extraction reagent (Thermo Fischer, Cat# 78833).…”

Section: Western Blottingmentioning

confidence: 99%

The stress specific impact of ALKBH1 on tRNA cleavage and tiRNA generation

Rashad

Han

Sato

et al. 2020

Preprint

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tiRNAs are small non-coding RNAs produced when tRNA is cleaved under stress. tRNA methylation modifications has emerged in recent years as important regulators for tRNA structural stability and sensitivity to cleavage and tiRNA generation during stress, however, the specificity and higher regulation of such a process is not fully understood. Alkbh1 is a m 1 A demethylase that leads to destabilization of tRNA and enhanced tRNA cleavage. We examined the impact of Alkbh1 targeting via gene knockdown or overexpression on B35 rat neuroblastoma cell line fate following stresses and on tRNA cleavage. We show that Alkbh1 impact on cell fate and tRNA cleavage is a stress specific process that is impacted by the demethylating capacity of the cellular stress in question. We also show that not all tRNAs are cleaved equally following Alkbh1 manipulation and stress, and that Alkbh1 KD fails to rescue tRNAs from cleavage following demethylating stresses. These findings shed a light on the specificity and higher regulation of tRNA cleavage and should act as a guide for future work exploring the utility of Alkbh1 as a therapeutic target for cancers or ischemic insult.

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Early BBB breakdown and subacute inflammasome activation and pyroptosis as a result of cerebral venous thrombosis

Cited by 54 publications

References 55 publications

Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair

Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair

Rapid Proteome Changes in Plasma and Cerebrospinal Fluid Following Bacterial Infection in Preterm Newborn Pigs

The stress specific impact of ALKBH1 on tRNA cleavage and tiRNA generation

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