IL-1β promotes transendothelial migration of PBMCs by upregulation of the FN/αβ signalling pathway in immortalised human brain microvascular endothelial cells.

Neuroinflammation is often associated with pathological changes in the function of the blood-brain barrier (BBB) caused by disassembly of tight and adherens junctions that under physiological conditions are important for the maintenance of the BBB integrity. Consequently, in inflammation the BBB becomes dysfunctional, facilitating leukocyte traversal of the barrier and accumulation of immune cells within the brain. The extracellular matrix (ECM) also contributes to BBB integrity but the significance of the main ECM receptors, the β integrins also expressed on endothelial cells, is less well understood. To evaluate whether β integrin function is affected during inflammation and impacts barrier function, we used a transformed human brain microvascular endothelial cell (THBMEC)-based Interleukin 1β (IL-1β)-induced inflammatory in vitro BBB model. We demonstrate that IL-1β increases cell-matrix adhesion and induces a redistribution of active β integrins to the basal surface. In particular, binding of αβ integrin to its ligand fibronectin is enhanced and αβ integrin-dependent signalling is upregulated. Additionally, localisation of the tight junction protein claudin-5 is altered. Blockade of the αβ integrin reduces the IL-1β-induced transendothelial migration of peripheral blood mononuclear cells (PBMCs). These data imply that IL-1β-induced inflammation not only destabilizes tight junctions but also increases αβ integrin-dependent cell-matrix adhesion to fibronectin.