TY - JOUR
T1 - Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling
AU - Schreibelt, Gerty
AU - Kooij, Gijs
AU - Reijerkerk, Arie
AU - van Doorn, Ruben
AU - Gringhuis, Sonja I
AU - van der Pol, Susanne
AU - Weksler, Babette B
AU - Romero, Ignacio A
AU - Couraud, Pierre-Olivier
AU - Piontek, Jörg
AU - Blasig, Ingolf E
AU - Dijkstra, Christine D
AU - Ronken, Eric
AU - de Vries, Helga E
PY - 2007/11
Y1 - 2007/11
N2 - The blood-brain barrier (BBB) prevents the entrance of circulating molecules and immune cells into the central nervous system. The barrier is formed by specialized brain endothelial cells that are interconnected by tight junctions (TJ). A defective function of the BBB has been described for a variety of neuroinflammatory diseases, indicating that proper regulation is essential for maintaining brain homeostasis. Under pathological conditions, reactive oxygen species (ROS) significantly contribute to BBB dysfunction and inflammation in the brain by enhancing cellular migration. However, a detailed study about the molecular mechanism by which ROS alter BBB integrity has been lacking. Here we demonstrate that ROS alter BBB integrity, which is paralleled by cytoskeleton rearrangements and redistribution and disappearance of TJ proteins claudin-5 and occludin. Specific signaling pathways, including RhoA and PI3 kinase, mediated observed processes and specific inhibitors of these pathways prevented ROS-induced monocyte migration across an in vitro model of the BBB. Interestingly, these processes were also mediated by protein kinase B (PKB/Akt), a previously unknown player in cytoskeleton and TJ dynamics that acted downstream of RhoA and PI3 kinase. Our study reveals new insights into molecular mechanisms underlying BBB regulation and provides novel opportunities for the treatment of neuroinflammatory diseases.
AB - The blood-brain barrier (BBB) prevents the entrance of circulating molecules and immune cells into the central nervous system. The barrier is formed by specialized brain endothelial cells that are interconnected by tight junctions (TJ). A defective function of the BBB has been described for a variety of neuroinflammatory diseases, indicating that proper regulation is essential for maintaining brain homeostasis. Under pathological conditions, reactive oxygen species (ROS) significantly contribute to BBB dysfunction and inflammation in the brain by enhancing cellular migration. However, a detailed study about the molecular mechanism by which ROS alter BBB integrity has been lacking. Here we demonstrate that ROS alter BBB integrity, which is paralleled by cytoskeleton rearrangements and redistribution and disappearance of TJ proteins claudin-5 and occludin. Specific signaling pathways, including RhoA and PI3 kinase, mediated observed processes and specific inhibitors of these pathways prevented ROS-induced monocyte migration across an in vitro model of the BBB. Interestingly, these processes were also mediated by protein kinase B (PKB/Akt), a previously unknown player in cytoskeleton and TJ dynamics that acted downstream of RhoA and PI3 kinase. Our study reveals new insights into molecular mechanisms underlying BBB regulation and provides novel opportunities for the treatment of neuroinflammatory diseases.
KW - Animals
KW - Cell Line, Transformed
KW - Humans
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Rats
KW - Reactive Oxygen Species/metabolism
KW - Signal Transduction
KW - Tight Junctions/metabolism
KW - rhoA GTP-Binding Protein/metabolism
U2 - https://doi.org/10.1096/fj.07-8329com
DO - https://doi.org/10.1096/fj.07-8329com
M3 - Article
C2 - 17586731
SN - 0892-6638
VL - 21
SP - 3666
EP - 3676
JO - FASEB Journal
JF - FASEB Journal
IS - 13
ER -