Expression of Chemokines and Their Receptors by Human Brain Endothelium: Implications for Multiple Sclerosis

Abstract

Leukocyte migration into the central nervous system (CNS) is mediated by chemokines expressed on CNS endothelial cell surfaces. This study investigated the production of chemokines and expression of chemokine receptors by human brain endothelial cells (HBECs) in vitro and in situ. Four chemokines (CCL2, CCL5, CXCL8, and CXCL10) were demonstrated by immunohistochemistry in endothelial cells in brain samples from patients with multiple sclerosis. CXCL8 and CCL2 were constitutively released and increased by primary HBECs and the brain endothelial cell line hCEMC/D3 in response to tumor necrosis factor and/or interferon gamma. CXCL10 and CCL5 were undetectable in resting endothelial cells but were secreted in response to these proinflammatory cytokines. Tumor necrosis factor strongly increased the production of CCL2, CCL5, and CXCL8; interferon gamma upregulated CXCL10 exclusively. CCL3 was not secreted by HBECs and seemed to be confined to astrocytes in situ. The chemokine receptors CXCR1 and CXCR3 were expressed by HBECs both in vitro and in situ; CXCR3 was upregulated in response to cytokine stimulation in vitro. In contrast, CXCR3 expression was reduced in noninflammatory (silent) multiple sclerosis lesions. The particularly high levels of CXCL10 and CXCL8 expressed by brain endothelium may contribute to the predominant TH1-type inflammatory response observed in chronic inflammatory conditions such as multiple sclerosis.

Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid

“…It is preferentially expressed on activated Th1 cells but also on astrocytes, microglia/monocytes, dendritic cells and natural killer cells [27,28]. This chemokine receptor is up-regulated in response to IFN-γ and TNF stimulation in vitro in human brain endothelial cells as well as in astrocytes and microglia [29,30]. At the same time CXCR3 expression is shown to be reduced in noninflammatory multiple sclerosis lesions and CXC3-positive cells were not detected in normal appearing white matter of MS brains [26,29,31].…”

“…This chemokine receptor is up-regulated in response to IFN-γ and TNF stimulation in vitro in human brain endothelial cells as well as in astrocytes and microglia [29,30]. At the same time CXCR3 expression is shown to be reduced in noninflammatory multiple sclerosis lesions and CXC3-positive cells were not detected in normal appearing white matter of MS brains [26,29,31]. Since targeting the chemokine signalling receptors might open up new therapeutic avenues for autoimmune diseases like MS, much effort have been made to find candidates for chemokine and chemokine receptor antagonism.…”

CCR2+CCR5+ T Cells Produce Matrix Metalloproteinase-9 and Osteopontin in the Pathogenesis of Multiple Sclerosis

“…In contrast, CCL2 was decreased in the CSF in MS during relapses (38,41), and this could be the result of consumption by CCR2 + cells (42). Moreover, the presence of CCL2 and CCL5 was recently demonstrated in endothelial cells in brain samples from MS (43). CCL2 and CCL5 appear to play a critical role in adhesions of the encephalitogenic T cells to brain endothelial cells in a model of EAE (44).…”

Inhibition of Glycogen Synthase Kinase 3β (GSK3β) Decreases Inflammatory Responses in Brain Endothelial Cells

“…Although endothelial cells of various vascular beds are the targets of pro-inflammatory molecules, the endothelium can produce a multitude of cytokines, chemokines, 35 or other molecules 36 that can affect barrier function in a paracrine fashion and promote inflammation. 37 Given the significant anti-inflammatory activity of GSK3␤ inhibition in macrophages and other cells, we analyzed such effects in BMVECs after TNF␣ stimulation.…”