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Author Notes:

Corresponding author: Manuel Yepes, Department of Neurology, Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, 615 Michael Street, Suite 505J, Atlanta, Georgia 30322, USA. Email: myepes@emory.edu.

The authors declare no conflict of interest.

Subjects:

Research Funding:

This work was supported in part by National Institutes of Health Grants NS-062073 and HL-095063 (to MY).

Keywords:

  • cerebral ischemia
  • fibroblast growth factor-inducible 14 (Fn14)
  • monocyte chemoattractant protein-1 (MCP-1)
  • neutrophils
  • tumor necrosis factor-like weak inducer of apoptosis (TWEAK)

The interaction between tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 promotes the recruitment of neutrophils into the ischemic brain

Tools:

Journal Title:

Journal of Cerebral Blood Flow and Metabolism

Volume:

Volume 30, Number 6

Publisher:

, Pages 1147-1156

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are expressed in endothelial cells and perivascular astrocytes. Here, we show that TWEAK induces a dose-dependent increase in the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) in astrocytes, and that this effect is mediated by its interaction with Fn14 via nuclear factor-κB pathway activation. Exposure to oxygen-glucose deprivation (OGD) conditions increases TWEAK and Fn14 mRNA expression in wild-type (Wt) astrocytic cultures. Likewise, incubation under OGD conditions induces the expression of MCP-1 in Wt astrocytes but not in astrocytes deficient on either TWEAK (TWEAK−/−) or Fn14 (Fn14−/−). We also found that TWEAK induces the passage of neutrophils to the abluminal side of an in vitro model of the blood–brain barrier. Our earlier studies indicate that cerebral ischemia increases the expression of TWEAK and Fn14 in the endothelial cell-basement membrane-astrocyte interface. Here, we report that middle cerebral artery occlusion increases the expression of MCP-1 and the recruitment of neutrophils into the ischemic tissue in Wt but not in TWEAK−/− or Fn14−/− mice. These novel results indicate that during cerebral ischemia, the interaction between TWEAK and Fn14 leads to the recruitment of leukocytes into the ischemic tissue.

Copyright information:

© 2010 Nature Publishing Group

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