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 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.
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 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.
Authors: Marcio Francisco Lehmann; Ana Paula Kallaur; Sayonara Rangel Oliveira; Daniela Frizon Alfieri; Franciele Delongui; Johnathan de Sousa Parreira; Maria Caroline Martins de Araújo; Carolina Rossato; Jéssica Tavares de Almeida; Larissa Moliterno Pelegrino; Erick Frank Bragato; Ana Lucia Cruz Fürstenberger Lehmann; Helena Kaminami Morimoto; Marcell Alysson Batisti Lozovoy; Andrea Name Colado Simão; Damácio Ramon Kaimen-Maciel; Edna Maria Vissoci Reiche Journal: Metab Brain Dis Date: 2015-09-11 Impact factor: 3.584
Authors: M W Miller; H Maniates; E J Wolf; M W Logue; S A Schichman; A Stone; W Milberg; R McGlinchey Journal: Brain Behav Immun Date: 2017-09-01 Impact factor: 7.217