Mechanisms of C-reactive protein-induced blood-brain barrier disruption.
OBJECTIVE
Increased mortality after stroke is associated with brain edema formation and high plasma levels of the acute phase reactant C-reactive protein (CRP). The aim of this study was to examine whether CRP directly affects blood-brain barrier stability and to analyze the underlying signaling pathways.


METHODS
We used a cell coculture model of the blood-brain barrier and the guinea pig isolated whole brain preparation.


RESULTS
We could show that CRP at clinically relevant concentrations (10 to 20 microg/mL) causes a disruption of the blood-brain barrier in both approaches. The results of our study further demonstrate CRP-induced activation of surface Fcgamma receptors CD16/32 followed by p38-mitogen-activated protein kinase-dependent reactive oxygen species formation by the NAD(P)H-oxidase. The resulting oxidative stress increased myosin light chain kinase activity leading to an activation of the contractile machinery. Blocking myosin light chain phosphorylation prevented the CRP-induced blood-brain barrier breakdown and the disruption of tight junctions.


CONCLUSIONS
Our data identify a previously unrecognized mechanism linking CRP and brain edema formation and present a signaling pathway that offers new sites of therapeutic intervention.
Kuhlmann
Christoph R W
CR
Institute of Physiology and Pathophysiology, Johannes Gutenberg University of Mainz, Mainz, Germany. luhmann@uni-mainz.de
Librizzi
Laura
L
Closhen
Dorothea
D
Pflanzner
Thorsten
T
Lessmann
Volkmar
V
Pietrzik
Claus U
CU
de Curtis
Marco
M
Luhmann
Heiko J
HJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001929:Brain Edema / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000378:metabolism; D006168:Guinea Pigs; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018994:Myosin Light Chains; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases