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(Stroke. 2009;40:1458.)
© 2009 American Heart Association, Inc.

Original Contributions

Mechanisms of C-Reactive Protein-Induced Blood–Brain Barrier Disruption

Christoph R.W. Kuhlmann, MD; Laura Librizzi, PhD; Dorothea Closhen, MD; Thorsten Pflanzner; Volkmar Lessmann, PhD; Claus U. Pietrzik, PhD; Marco de Curtis, MD Heiko J. Luhmann, PhD

From the Institute of Physiology and Pathophysiology (C.R.W.K., D.C., V.L., H.J.L.), Johannes Gutenberg University of Mainz, Mainz, Germany; the Department of Experimental Neurophysiology (L.L., M.d.C.), Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta via Celoria 11, Milan, Italy; the Institute for Physiological Chemistry and Pathobiochemistry (T.P., C.U.P.), Johannes Gutenberg University of Mainz, Mainz, Germany; and the Institute for Physiology (V.L.), Otto-von-Guericke University, Magdeburg, Germany.

Correspondence to Heiko J. Luhmann, PhD, Johannes Gutenberg University of Mainz, Institute of Physiology and Pathophysiology, Duesbergweg 6, 55128 Mainz, Germany. E-mail luhmann{at}uni-mainz.de

Background and Purpose— 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 µg/mL) causes a disruption of the blood–brain barrier in both approaches. The results of our study further demonstrate CRP-induced activation of surface Fc 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.

Supplemental Methods