Caveolae/lipid raft modulates TNF‐alpha‐induced upregulation of cell adhesion molecules in human brain endothelial cells

Abstract

The blood‐brain barrier (BBB) is a physical and metabolic barrier separating the microenvironment of the central nervous system (CNS) from the peripheral circulation. Accumulating evidence suggests that TNF‐α plays a pivotal role in the activation of brain endothelium leading to the disruption of BBB and neuroinflammation. Exposure of human brain endothelial cells to TNF‐α increased expression of ICAM‐1 and VCAM‐1as well as elevated adhesion of brain endothelial cells to leukocytes. These effects were blocked by disruption of caveolae/lipid raft structure by cholesterol depleting agents or silencing of caveolin‐1. In addition, TNF‐α‐induced upregulation of CAMs was impeded by inhibitors to caveolae/lipid raft‐associated signaling molecules, such as Src kinase, NADPH oxidases (NOX), and nitric oxide synthases. The results in this study suggest that TNF‐alpha induces CAMs expression in human brain endothelium through NOX‐mediated generation of reactive oxygen species in caveolae/lipid raft domain. Therefore, selective targeting of lipid raft/caveolae‐mediated NOX in TNF‐alpha‐dependent brain endothelial inflammation may lessen adverse effects of neuroinflammation as well as neurodegenerative diseases. Supported in part by NIH grants (P42 ES 07380, MH63022, MH072567, and NS39254) and the American Heart Association (09SDG2300037).