TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model

Abstract

The blood-brain barrier (BBB) is a selective barrier and a functional gatekeeper for the central nervous system (CNS), essential for maintaining brain homeostasis. The BBB is composed of specialized brain endothelial cells (BECs) lining the brain capillaries. The tight junctions formed by BECs regulate paracellular transport, whereas transcellular transport is regulated by specialized transporters, pumps and receptors. Cytokine-induced neuroinflammation, such as the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), appear to play a role in BBB dysfunction and contribute to the progression of Alzheimer’s disease (AD) by contributing to amyloid-β (Aβ) peptide accumulation. Here, we investigated whether TNF-α and IL-1β modulate the permeability of the BBB and alter Aβ peptide transport across BECs. We used a human BBB in vitro model based on the use of brain-like endothelial cells (BLECs) obtained from endothelial cells derived from CD34+ stem cells cocultivated with brain pericytes. We demonstrated that TNF-α and IL-1β differentially induced changes in BLECs’ permeability by inducing alterations in the organization of junctional complexes as well as in transcelluar trafficking. Further, TNF-α and IL-1β act directly on BLECs by decreasing LRP1 and BCRP protein expression as well as the specific efflux of Aβ peptide. These results provide mechanisms by which CNS inflammation might modulate BBB permeability and promote Aβ peptide accumulation. A future therapeutic intervention targeting vascular inflammation at the BBB may have the therapeutic potential to slow down the progression of AD.

Lung infection byP. aeruginosainduces neuroinflammation and blood-brain barrier dysfunction in mice

“…It is known that lung infection or injury is associated with various neurological complications, from altered memory to cognitive decline (51–54). In our model, even in the absence of direct penetration of PA into the brain, infected mice developed anxiety-like behaviors, which might result from cerebral microvascular dysfunction, BBB leakage, and systemic/local production of cytotoxic cytokines like IL-1β (55–57) and TNF-α (47, 58) as previously documented.…”

“…Indeed, previous studies have demonstrated a correlation between in vivo administration of proinflammatory cytokines and BBB leakage (39,43). The ability of cytokines to open the paracellular pathway of endothelial barrier has been attributed to endothelial cytoskeleton reorganization (24) and/or downregulation of junction protein expression (22,40,(44)(45)(46)(47)(48)(49)(50).…”

Lung infection by P. aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice

“…Indeed, previous studies have demonstrated a correlation between in vivo administration of pro-in ammatory cytokines and BBB leakage (39,43). The ability of cytokines to open the paracellular pathway of endothelial barrier has been attributed to endothelial cytoskeleton reorganization (24) and/or downregulation of junction protein expression (22,40,(44)(45)(46)(47)(48)(49)(50).…”

TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1

“…To our knowledge, this is the first time that similar effects have been reported in HBP. In the endothelial cells of the BBB, we and others have reported that TNFα decreases ABCB1 and ABCG2 expression and functionality, thus suggesting different mechanisms of regulation in these cell types [ 48 , 64 ]. We have previously reported the upregulation of ABCB1 when the LXR signaling pathway is activated by natural or synthetic agonist in endothelial BBB cells [ 36 ].…”

“…When ready, HBP were rinsed once with warm DMEM/HG/0.1% BSA and then incubated in DMEM/HG/0.1% BSA supplemented or not with 5 or 10 ng/mL of TNFα. These concentrations were selected based on previous in vitro studies published by us and others [ 64 , 65 , 66 , 67 ].…”