Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair
- PDF / 2,040,753 Bytes
- 19 Pages / 595.276 x 790.866 pts Page_size
- 79 Downloads / 127 Views
(2020) 17:267
RESEARCH
Open Access
Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair Hila Israelov1†, Orly Ravid1†, Dana Atrakchi1, Daniel Rand1,2, Shirin Elhaik1, Yael Bresler1,2, Rachel Twitto-Greenberg1,2, Liora Omesi1, Sigal Liraz-Zaltsman1,3,4, Fabien Gosselet5, Michal Schnaider Beeri1,6,7 and Itzik Cooper1,6,8*
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. (Continued on next page)
* Correspondence: [email protected] † Hila Israelov and Orly Ravid contributed equally to this work. 1 The Joseph Sagol Neuroscience Center, Sheba Medical Center, 52621 Tel Hashomer, Ramat Gan, Israel 6 School of Psychology, Interdisciplinary Center (IDC), Herzliya, Israel Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from
Data Loading...
