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

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 g/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.

CRP regulates the expression and activity of tissue factor as well as tissue factor pathway inhibitor via NF‐κB and ERK 1/2 MAPK pathway

“…For example, a study from Kuhlmann et al found that CRP could cause a disrup- tion of the blood-brain barrier via activation of surface Fcgamma receptors CD16/32 followed by p38-MAPK-dependent reactive oxygen species formation by the NAD(P)H-oxidase [29], which was demonstrated in bovine brain microvascular endothelial cells [32]. Consequently, regulation of gene expression by CRP is complex and expression of different gene in the same cell model or same gene in different cell models may be regulated via different pathways.…”

C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage

“…Apart from activating microglia and complement C3, 23 CRP can directly cause blood-brain barrier disruption and brain edema formation. 24 Experimental studies demonstrate that an acute local inflammatory response to the hematoma can occur within 1 hour of onset, 25 and a systemic state of inflammation is triggered. 5 It seems likely that plasma CRP reflects evolving proinflammatory processes, induced locally and systemically.…”

Plasma Antioxidant Activity as a Marker for a Favourable Outcome in Acute Ischemic Stroke

“…As among the pathological processes in acute ischemic stroke are inflammation, neuronal and glial injury, CRP concentration in plasma was estimated throughout to correlate with and predict infarct growth in acute ischemic stroke and stroke progression. The elevated plasma level is currently accepted as an outcome-predicting factor at IS (Di Napoli et al, 2001;Kuhlmann et al, 2009). We prospectively measured the CRP concentration in plasma of IS patients in our study ( 24 hours from symptom onset) and compared it with the CRP plasma level of healthy persons.…”

“…However, the question whether the elevated CRP levels are induced by stroke or reflect preexisting inflammatory conditions is still open. Recently, participation of CRP in blood-brain barrier disruption and its mechanisms are specified by Kuhlman (Kuhlmann et al, 2009). It was shown that the clinically relevant concentrations 10 and 20 μg/ml cause a disruption of BBB in a cell coculture BBB model and in the guinea pig isolated whole brain preparation.…”