ZO-1 expression is suppressed by GM-CSF via miR-96/ERG in brain microvascular endothelial cells

• Published in: Journal of cerebral blood flow and metabolism Vol. 38; no. 5; pp. 809 - 822
• Main Authors: Zhang, Hu, Zhang, Shuhong, Zhang, Jilin, Liu, Dongxin, Wei, Jiayi, Fang, Wengang, Zhao, Weidong, Chen, Yuhua, Shang, Deshu
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.05.2018
• Subjects: Animals; Blood-Brain Barrier - metabolism; Endothelial Cells - metabolism; Gene Expression Regulation - physiology; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Male; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; Oncogene Proteins - metabolism; Original; Transcriptional Regulator ERG - metabolism; Zonula Occludens-1 Protein - biosynthesis; Brain microvascular endothelial cells; miR-96; ZO-1; ERG; GM-CSF; c-MYC
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X17702668

The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases in some disorders such as vascular dementia, Alzheimer’s disease, and multiple sclerosis. We previously reported that in Alzheimer’s disease patients, a high level of GM-CSF in the brain parenchyma downregulated expression of ZO-1, a blood–brain barrier tight junction protein, and facilitated the infiltration of peripheral monocytes across the blood–brain barrier. However, the molecular mechanism underlying regulation of ZO-1 expression by GM-CSF is unclear. Herein, we found that the erythroblast transformation-specific (ETS) transcription factor ERG cooperated with the proto-oncogene protein c-MYC in regulation of ZO-1 transcription in brain microvascular endothelial cells (BMECs). The ERG expression was suppressed by miR-96 which was increased by GM-CSF through the phosphoinositide-3 kinase (PI3K)/Akt pathway. Inhibition of miR-96 prevented ZO-1 down-regulation induced by GM-CSF both in vitro and in vivo. Our results revealed the mechanism of ZO-1 expression reduced by GM-CSF, and provided a potential target, miR-96, which could block ZO-1 down-regulation caused by GM-CSF in BMECs.