Abstract
The glio-vascular unit (G-unit) plays a prominent role in maintaining homeostasis of the blood-brain barrier (BBB) and disturbances in cells forming this unit may seriously dysregulate BBB. The direct and indirect effects of cytokines on cellular components of the BBB are not yet unclear. The present study compares the effects of cytokines and cytokine-treated astrocytes on brain endothelial barrier. 3-dimensional transwell co-cultures of brain endothelium and related-barrier forming cells with astrocytes were used to investigate gliovascular barrier responses to cytokines during pathological stresses. Gliovascular barrier was measured using trans-endothelial electrical resistance (TEER), a sensitive index of in vitro barrier integrity. We found that neither TNF-α, IL-1β or IFN-γ directly reduced barrier in human or mouse brain endothelial cells or ECV-304 barrier (independent of cell viability/metabolism), but found that astrocyte exposure to cytokines in co-culture significantly reduced endothelial (and ECV-304) barrier. These results indicate that the barrier established by human and mouse brain endothelial cells (and other cells) may respond positively to cytokines alone, but that during pathological conditions, cytokines dysregulate the barrier forming cells indirectly through astrocyte activation involving reorganization of junctions, matrix, focal adhesion or release of barrier modulating factors (e.g. oxidants, MMPs).
Highlights
The blood brain barrier (BBB) is a unique astrocytecapillary-endothelial complex which maintains CNS homeostatic fluid balance, and serves as a first line of defense protecting the brain and parenchyma against pathogens, as well as blood-borne leukocytes and hormones, neurotransmitters and pro-inflammatory cytokines and chemokines [1,2]
Several reports have indicate that astrocytes co-cultured with endothelial cells or astrocyte-conditioned media improve endothelial barrier integrity, the potential effects of astrocytes on the cerebral endothelial cells during CNS stress contributing to the pathological loss of BBB are not yet as well understood [20]
The mechanisms through which factors secreted by stressed astrocytes dysregulate endothelial barrier during pathologies e.g. cerebral ischemia remains an area under intensive investigation [42]
Summary
The blood brain barrier (BBB) is a unique astrocytecapillary-endothelial complex which maintains CNS homeostatic fluid balance, and serves as a first line of defense protecting the brain and parenchyma against pathogens, as well as blood-borne leukocytes and hormones, neurotransmitters and pro-inflammatory cytokines and chemokines [1,2]. Several reports have indicate that astrocytes co-cultured with endothelial cells or astrocyte-conditioned media improve endothelial barrier integrity, the potential effects of astrocytes on the cerebral endothelial cells during CNS stress contributing to the pathological loss of BBB are not yet as well understood [20]. TNF-a can either increase or decrease solute exchange depending on the type of insult in porcine renal epithelial cells (LLC-PK1) [48,49] These effects are mediated by diverse mechanisms involving actin reorganization, monolayer motility, NF-kb activation, apoptosis and reorganization of junctional proteins [49,50,51,52,53,54]. The differential roles of astrocytes and cytokines in modulating brain endothelial barrier properties are discussed
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