TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia

Tumor necrosis factor- like weak inducer of apoptosis ( TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit ( NVU) during cerebral ischemia, TWEAK activity was inhibited in wild- type mice with a soluble Fn14- Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion ( MCAO). Administration of Fn14- Fc decoy resulted in faster recovery of motor function and a 66.4% +/- 610% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1% 613.1% decrease when animals were treated 1 h later ( n= 4, P < 0.05). Genetic deficiency of Fn14 resulted in a 60% +/- 612.8% decrease in the volume of the ischemic lesion ( n= 6, P < 0.05), and a 87% 622% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult ( n= 6, P < 0.005). Compared with control animals, treatment with Fn14- Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor- jB pathway activation, matrix metalloproteinase- 9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.