Activation of brain endothelial cells by interleukin-1 is regulated by the extracellular matrix after acute brain injury.
Molecular and Cellular Neuroscience. 2013-11-01; 57: 93-103
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1. Mol Cell Neurosci. 2013 Nov;57:93-103. doi: 10.1016/j.mcn.2013.10.007. Epub 2013
Activation of brain endothelial cells by interleukin-1 is regulated by the
extracellular matrix after acute brain injury.
Summers L(1), Kangwantas K, Rodriguez-Grande B, Denes A, Penny J, Kielty C,
(1)Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
The extracellular matrix (ECM) of the central nervous system (CNS) is essential
for normal brain function, whilst ECM remodelling is associated with
cerebrovascular inflammation driven by the cytokine interleukin-1 (IL-1) after
acute brain injury. The effect of ECM remodelling on endothelial activation
during neuroinflammation remains unknown. Here we report that ECM remodelling in
the cerebrovasculature critically regulates IL-1-induced endothelial cell
activation after cerebral ischaemia; Expression levels of ECM molecules
associated with the cerebrovasculature, namely fibronectin (FN) and collagen IV
(Col IV), strongly increased in brain blood vessels after middle cerebral artery
occlusion (MCAo) in a time-dependent manner, reaching a peak of vascular
expression 48 h after MCAo. In cultures, FN and Col IV (but also laminin-1 and
fibrillin-1) promoted strong attachment of the GPNT endothelial cell line and
primary rat brain endothelial cells, which was markedly inhibited by RGD
(Arg-Gly-Asp) peptide, or specific integrin β1, α4, α5 and αv blockade.
IL-1β-induced activation of extracellular-regulated kinase 1/2 (ERK1/2) and
nuclear factor κB (NFκB), and synthesis of cytokine-induced neutrophil
chemoattractant (CINC-1) were enhanced in cells plated onto ECM molecules, and
these responses were inhibited by selective integrin blockade. Finally, increased
ECM expression in vessels after MCAo was found associated with vinculin
clustering, increased integrin β1 expression, and increased IL-1 receptor
associated kinase-1 (IRAK-1) activity in endothelial cells and perivascular
astrocytes. Therefore, our data indicate a novel function for the ECM in the
regulation of cerebrovascular inflammation triggered by IL-1 during acute brain
PMID: 24161715 [Indexed for MEDLINE]