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

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.

Bibliometric Analysis of the Inflammasome and Pyroptosis in Brain

“…Inflammasome is not only involved in brain diseases but also involved in other multiple diseases, including sepsis, cardiovascular disease, liver diseases, and acute myeloid leukemia ( Chen et al, 2019b ; Guo et al, 2019 ; Israelov et al, 2020 ; Johnson et al, 2018 ; Zeng et al, 2019 ). The mechanism and function of inflammasome in other diseases also have important implications for the study of that in the brain.…”

“…Pyroptosis is related to multiple diseases and can be involved in a variety of acute and chronic injuries ( Alfonso-Loeches et al, 2014 ; Israelov et al, 2020 ; Xu et al, 2019 ; Zeng et al, 2019 ). In recent years, studies have found that inflammation is widely found in the various central nervous system (CNS) diseases ( Figure 1 ), and the occurrence and development of traumatic brain injuries (TBI) ( de Rivero Vaccari et al, 2009 ; Liu et al, 2018 ; Chen et al, 2019c ; Irrera et al, 2020 ), stroke ( Abulafia et al, 2009 ; Poh et al, 2019 ), Alzheimer’s disease (AD) ( Halle et al, 2008 ; Flores et al, 2018 ), Parkinson’s disease (PD) ( Codolo et al, 2013 ; Yan et al, 2020 ), multiple sclerosis (MS) ( Soulika et al, 2009 ; McKenzie et al, 2018 ), Huntington’s disease (HD) ( Glinsky, 2008 ; Paldino et al, 2020 ), spinal cord injury (SCI) ( de Rivero Vaccari et al, 2008 ; de Rivero Vaccari et al, 2012 ; Jiao et al, 2020 ), and other diseases depend on the inflammasome.…”

Beta-Secretase 1 Underlies Reactive Astrocytes and Endothelial Disruption in Neurodegeneration

“…In addition, BACE1 inhibitor prevented the nuclear condensation and reduce the IL-1β proinflammatory marker not only in astrocytes as well as recovered co-cultured ECs, reducing GAPs that are more related with extravasation and inflammation than with cell death (Hirata et al, 1995;Israelov et al, 2020). In the case of the ECs, our data showed that the percentage of released LDH after glutamate treatment was very low contrasted with nuclear condensation levels, since chromatin condensation occurs in the early stages of excitotoxicity prior to the disruption of the plasma membrane and the release of LDH, that occurs later in an advanced cell detriment (Bezvenyuk et al, 2003;Elmore, 2007).…”

“…The gaps are visualized as spaces between ECs indicate damage in the cell monolayer. This term was defined as: disruption of endothelial cells involving extravasation (Hirata et al, 1995) and inflammation more than cell death (Israelov et al, 2020).…”

Astragaloside IV Reduces Cerebral Ischemia/Reperfusion-Induced Blood-Brain Barrier Permeability in Rats by Inhibiting ER Stress-Mediated Apoptosis

“…Destruction of the blood-brain barrier (BBB) is a common pathological feature of many nervous diseases [1,2]. Under physiological conditions, it preserves proper homeostasis of the brain by highly specialized selection [3]. However, BBB dysfunction or structural disruption after cerebral ischemia/ reperfusion (I/R) may lead to irreversible neuronal damage and brain dysfunction [4].…”