Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury

Abstract

The chemokine CCL2 is considered as one of the main effectors driving postischemic infiltration of monocytes into the brain parenchyma. New experimental data, however, suggest that CCL2 could also participate in blood-brain barrier (BBB) 'opening' during the transmigration of monocytes. The current study examines the role of CCL2 in regulating BBB permeability after ischemia in vitro. To address this issue, an in vitro BBB model (coculture of astrocytes and brain endothelial cells) was subjected to 5 h of oxygen glucose deprivation, followed by reoxgenation (in vitro ischemia/ reperfusion (I/R)) for 0 to 48 h. During reperfusion, there was a biphasic enhancement of barrier permeability, with a 200-fold increase in barrier permeability to FITC-albumin at 6 h and a further period of disruption around 24 h. The latter coincided with increased secretion of CCL2 by both astrocytes and brain endothelial cells and increased levels of the CCL2 receptor, CCR2. Applying antisense oligonucleotide or neutralizing antibody to block CCL2 significantly decreased I/Rinduced enhancement of BBB permeability (approximately twofold) and redistribution of tightjunction (TJ) proteins (occludin, zonula occluden-1, 2, claudin-5). Similarly, absence of CCR2 from endothelial cells caused stabilization of TJ complexes and decreased the permeability of brain endothelial barrier during in vitro I/R. These data suggest CCL2/CCR2 has an important role in regulating brain endothelial permeability and might be a potential novel therapeutic target for stroke.

Deleterious Effects of Dihydrotestosterone on Cerebral Ischemic Injury

“…Inhibition of adhesion molecules and chemokines reduces experimental stroke damage, in part by depressing recruitment of peripheral inflammatory cells into injured brain (Takami et al, 2001;Zhang et al, 1994;Zhang et al, 1995). For example, the chemokine Ccl2 not only contributes to postischemic inflammation but also confers damage to the blood-brain barrier (Dimitrijevic et al, 2006). In this subcategory, DHT induction of Cox-2 is of interest, as ischemic neuronal damage is enhanced through inflammation and Na + -Ca 2 + homeostasis via activation of E-prostanoid receptor 1 receptor by prostaglandin E 2 (Kawano et al, 2006).…”

Role of CCR2 in Inflammatory Conditions of the Central Nervous System

“…Absence of CCR2 and CCL2 owing to treatment with neutralizing antibodies decreases the permeability of the brain endothelial barrier during in vitro ischemia-reperfusion. 51 Furthermore, CCR2-deficient mice are reported to have smaller infarcts, reduced blood-brain barrier permeability and reduced expression of inflammatory cytokines after ischemia-reperfusion compared with wild-type littermate controls. 52 Another study has shown that, compared with wild-type animals, CCR2-deficient mice have reduced levels of macrophages and neutrophils in the ischemic brain after ischemia-reperfusion, but without any difference in infarct volume.…”

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

“…By binding to their specific Gprotein-coupled receptors, chemokines induce cell-specific migration and activation of immune cells (Glabinski et al, 1996;Hulkower et al, 1993;Lahrtz et al, 1998;Miller and Meucci, 1999). Monocyte chemoattractant protein-1 (MCP1; officially known as C-C motif chemokine 2, CCL2) is one of the most highly and transiently expressed chemokines in many central nervous system (CNS) injuries, including ischemia, hemorrhage and excitotoxic injury (Capoccia et al, 2008;Dimitrijevic et al, 2006;Frangogiannis et al, 2007;Hanisch, 2002;Kim et al, 2008;Morimoto et al, 2008;Sheehan et al, 2007;Yan et al, 2007). The rodent MCP1 differs from the human protein at the C-terminus, with the rodent protein having a longer highly glycosylated Cterminus.…”