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

Authors
  • Israelov, Hila1
  • Ravid, Orly1
  • Atrakchi, Dana1
  • Rand, Daniel1, 2
  • Elhaik, Shirin1
  • Bresler, Yael1, 2
  • Twitto-Greenberg, Rachel1, 2
  • Omesi, Liora1
  • Liraz-Zaltsman, Sigal1, 3, 4
  • Gosselet, Fabien5
  • Schnaider Beeri, Michal1, 6, 7
  • Cooper, Itzik1, 6, 8
  • 1 Sheba Medical Center, Tel Hashomer, Ramat Gan, 52621, Israel , Tel Hashomer (Israel)
  • 2 Tel-Aviv University, Tel Aviv, Israel , Tel Aviv (Israel)
  • 3 The Hebrew University of Jerusalem, Jerusalem, Israel , Jerusalem (Israel)
  • 4 Ono Academic College, Kiryat Ono, Israel , Kiryat Ono (Israel)
  • 5 Artois University, Lens, F-62300, France , Lens (France)
  • 6 Interdisciplinary Center (IDC), Herzliya, Israel , Herzliya (Israel)
  • 7 The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA , New York (United States)
  • 8 Sheba Medical Center, Tel-Hashomer, Israel , Tel-Hashomer (Israel)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 09, 2020
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12974-020-01927-w
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundExcessive 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.MethodsAn 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.ResultsPX 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.ConclusionsThese 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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