Disruption of in vitro endothelial barrier integrity by Japanese encephalitis virus‐Infected astrocytes. Issue 11 (8th May 2015)

• Record Type: Journal Article
• Authors: Chang, Cheng‐Yi; Li, Jian‐Ri; Chen, Wen‐Ying; Ou, Yen‐Chuan; Lai, Ching‐Yi; Hu, Yu‐Hui; Wu, Chih‐Cheng; Chang, Chen‐Jung; Chen, Chun‐Jung
• Is Part Of: Glia. Volume 63:Issue 11(2015:Nov.)
• Page Start: 1915
• Page End: 1932
• Publication Date: 2015-05-08
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22857
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Blood–brain barrier (BBB) characteristics are induced and maintained by crosstalk between brain microvascular endothelial cells and neighboring cells. Using <italic>in vitro</italic> cell models, we previously found that a bystander effect was a cause for Japanese encephalitis‐associated endothelial barrier disruption. Brain astrocytes, which neighbor BBB endothelial cells, play roles in the maintenance of BBB integrity. By extending the scope of relevant studies, a potential mechanism has been shown that the activation of neighboring astrocytes could be a cause of disruption of endothelial barrier integrity during the course of Japanese encephalitis viral (JEV) infection. JEV‐infected astrocytes were found to release biologically active molecules that activated ubiquitin proteasome, degraded zonula occludens‐1 (ZO‐1) and claudin‐5, and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. JEV infection caused astrocytes to release vascular endothelial growth factor (VEGF), interleukin‐6 (IL‐6), and matrix metalloproteinases (MMP‐2/MMP‐9). Our data demonstrated that VEGF and IL‐6 released by JEV‐infected astrocytes were critical for the proteasomal degradation of ZO‐1 and the accompanying disruption of endothelial barrier integrity through the activation of Janus kinase‐2 (Jak2)/signal transducer and activator of transcription‐3 (STAT3) signaling as well as the induction of ubiquitin–protein ligase E3 component, <italic>n</italic>‐recognin‐1 (Ubr 1) in endothelial cells. MMP‐induced endothelial barrier disruption was accompanied by MMP‐mediated proteolytic degradation of claudin‐5 and ubiquitin proteasome‐mediated degradation of ZO‐1 via extracellular VEGF release. Collectively, these data suggest that JEV infection could activate astrocytes and cause release of VEGF, IL‐6, and MMP‐2/MMP‐9, thereby contributing, in a concerted action, to the induction of Japanese encephalitis‐associated BBB breakdown. GLIA 2015;63:1915–1932</p> </abstract>