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Open Access 01-12-2020 | Research

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

Authors: Hila Israelov, Orly Ravid, Dana Atrakchi, Daniel Rand, Shirin Elhaik, Yael Bresler, Rachel Twitto-Greenberg, Liora Omesi, Sigal Liraz-Zaltsman, Fabien Gosselet, Michal Schnaider Beeri, Itzik Cooper

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

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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Title: Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair
Authors: Hila Israelov
Orly Ravid
Dana Atrakchi
Daniel Rand
Shirin Elhaik
Yael Bresler
Rachel Twitto-Greenberg
Liora Omesi
Sigal Liraz-Zaltsman
Fabien Gosselet
Michal Schnaider Beeri
Itzik Cooper
Publication date: 01-12-2020
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01927-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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