Exacerbation of oxygen–glucose deprivation-induced blood–brain barrier disruption: potential pathogenic role of interleukin-9 in ischemic stroke

2017 ◽  
Vol 131 (13) ◽  
pp. 1499-1513 ◽  
Author(s):  
Sha Tan ◽  
Yilong Shan ◽  
Yuge Wang ◽  
Yinyao Lin ◽  
Siyuan Liao ◽  
...  

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood–brain barrier (BBB) following oxygen–glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylated protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.

2020 ◽  
Vol 13 (626) ◽  
pp. eaay5686 ◽  
Author(s):  
Feifei Ma ◽  
Ping Sun ◽  
Xuejing Zhang ◽  
Milton H. Hamblin ◽  
Ke-Jie Yin

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.


Stroke ◽  
2005 ◽  
Vol 36 (5) ◽  
pp. 1059-1064 ◽  
Author(s):  
Karim Benchenane ◽  
Vincent Berezowski ◽  
Mónica Fernández-Monreal ◽  
Julien Brillault ◽  
Samuel Valable ◽  
...  

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Himakarnika Alluri ◽  
Robert Patrick Clayton ◽  
Devendra Sawant ◽  
Hayden W Stagg ◽  
Rickesha L Wilson ◽  
...  

2008 ◽  
Vol 328 (2) ◽  
pp. 487-495 ◽  
Author(s):  
Sharanya Vemula ◽  
Karen E. Roder ◽  
Tianzhi Yang ◽  
G. Jayarama Bhat ◽  
Thomas J. Thekkumkara ◽  
...  

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