Abstract
Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood–brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood–brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood–brain barrier stabilization.
Highlights
The blood–brain barrier (BBB) is a complex multicellular interface between blood and central nervous system (CNS) tissue that tightly controls the exchange of soluble and cellular factors
The G-protein coupled receptor CXC receptor 2 (CXCR2) can be found on neutrophils, T lymphocytes, and basophils but it is expressed on non-hematopoietic cells including oligodendrocytes and endothelium [4,5,6]
Quantitative real-time PCR revealed a substantial increase of basal CXCR2 mRNA expression 4 h after starting stimulation with tumor necrosis factor-α (TNFα) or interleukin-1β (IL1β; Figure 1A)
Summary
The blood–brain barrier (BBB) is a complex multicellular interface between blood and central nervous system (CNS) tissue that tightly controls the exchange of soluble and cellular factors The border between both compartments is formed by highly specialized endothelial cells connected by tight junctions (TJ). CXCL5 has been found to be elevated in patients with gadolinium-enhancing magnetic resonance imaging (MRI) lesions, reflecting acute disturbance of the BBB, in comparison to MS patients with inactive disease [8]. This link to disease activity, partly even before clinical manifestation, suggests a potential role of ELR+ CXC chemokines in the chronological sequence of MS lesion formation. We investigated the effects of CXCR2-binding chemokines CXCL5 and CXCL8 on brain endothelial tight junction morphology and barrier function in vitro
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