Pro-Inflammatory Cytokines Modulate Matrix Metalloproteinase Secretion and Organic Anion Transport at the Blood-Cerebrospinal Fluid Barrier

Abstract

Neuroinflammation and neuroinfection trigger cytokine-mediated responses that include an increase in the cerebrospinal fluid (CSF) levels of pro-inflammatory matrix metalloproteinases (MMPs) and organic anions such as leukotrienes and prostaglandins. The choroid plexus (CP) epithelium forming the interface between the blood and the CSF regulates the CSF concentration of bioactive organic anions and is involved in neuro-immune regulation. We demonstrated that both fourth and lateral ventricle CPs are a source of pro- and active MMP-2 and MMP-9 in the brain. Using a cellular model of the blood-CSF barrier, we showed that a pro-inflammatory cytokine treatment leads to an increase in the choroidal MMP secretion at either the apical or the basolateral membrane, depending on the ventricular origin of the choroidal cells. This effect was not concomitant with an alteration in the structural blood-CSF barrier. Neither was the pool of antioxidant sulfhydryls in the choroidal cells challenged. In contrast, the efficiency of the choroidal epithelium to clear the CSF from organic anions was highly reduced. Thus, during inflammation, the CPs could be one source of MMPs found in the CSF facilitate leucocyte migration by secreting MMPs into the choroidal stroma, and promote the inflammatory process by failing in its ability to clear deleterious compounds from the brain.

Multiple expression of matrix metalloproteinases in murine neurocysticercosis: Implications for leukocyte migration through multiple central nervous system barriers

“…These findings complement a recent report showing the lack of structural changes in junctional complexes of the CPs of animals infected with M. corti [3]. These results are consistent with previous observations in an in vitro model showing that exposure to pro-inflammatory cytokines increased MMP-9 secretion by the choroidal epithelium and led to functional differences in permeability but not structural changes of the junctional complexes [50] although the permeability changes in this model may have been more notable. The ability to maintain the integrity of junctional complex proteins together with the more limited activity of MMPs in the CPs helps to explain why the CPs are a limited source of inflammatory cells in the CNS during infection.…”

Differential changes in junctional complex proteins suggest the ependymal lining as the main source of leukocyte infiltration into ventricles in murine neurocysticercosis

“…In rats with fluid shifts induced by head-down tilts there were no alterations in the TJs at the ultrastructural level or by immunofluorescence microscopy (Masseguin et al, 2001). Also, in vitro cultures of choroidal cells treated with pro-inflammatory cytokines induced expression of active MMP-9 and MMP-2, but even under these conditions no alterations in the expression of TJ proteins were detected (Strazielle et al, 2003). In a study of experimental autoimmune encephalitis (EAE) the fenestrated capillaries of the CP remained intact, adhesion molecules ICAM-1 and VCAM-1 were not induced in these vessels and leukocyte migration across the endothelium could not be detected .…”

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

“…Access to the brain is strictly controlled by blood-brain interfaces, blood vessels and the choroid plexus, and accumulation in neural tissue may result from the enhanced entry/reduced exit rates of T cells from the brain (Kleine and Benes, 2006;Bechmann et al, 2007;Engelhardt and Ransohoff, 2005). The activation process has a dramatic effect on this pathway, in particular by modulating the expression of the adhesion molecules, metalloproteases and chemokine receptors required for lymphocyte transendothelial migration and crawling in inflamed tissue del Pozo et al, 1995;Giraudon et al, 1997;Lane et al, 2000;Strazielle et al, 2003). As a result, more resting T-cells are found in lymphoid organs while activated T-cells mainly target nonlymphoid organs, including brain (Westermann et al, 2005).…”