Mechanisms of C-reactive protein-induced blood-brain barrier disruption

C. R W Kuhlmann, Laura Librizzi, Dorothea Closhen, Thorsten Pflanzner, Volkmar Lessmann, Claus U. Pietrzik, Marco De Curtis, Heiko J. Luhmann

Research output: Contribution to journalArticle

Abstract

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 Fcγ 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.

Original languageEnglish
Pages (from-to)1458-1466
Number of pages9
JournalStroke
Volume40
Issue number4
DOIs
Publication statusPublished - Apr 1 2009

Keywords

  • Blood-brain barrier
  • Edema
  • Myosin light chain
  • Stroke

ASJC Scopus subject areas

  • Medicine(all)
  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

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  • Cite this

    Kuhlmann, C. R. W., Librizzi, L., Closhen, D., Pflanzner, T., Lessmann, V., Pietrzik, C. U., De Curtis, M., & Luhmann, H. J. (2009). Mechanisms of C-reactive protein-induced blood-brain barrier disruption. Stroke, 40(4), 1458-1466. https://doi.org/10.1161/STROKEAHA.108.535930