Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Increases the Permeability of the Neurovascular Unit through Nuclear Factor-κB Pathway Activation

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts on responsive cells via binding to a small cell-surface receptor named fibroblast growth factor-inducible-14 (Fn14). TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production. The present study investigated whether TWEAK plays a role in the regulation of the permeability of the neurovascular unit (NVU). We found that intracerebral injection of TWEAK in wild-type mice induces activation of the nuclear factor-κB (NF-κB) pathway and matrix metalloproteinase-9 (MMP-9) expression in the brain with resultant disruption in the structure of the NVU and increase in the permeability of the blood-brain barrier (BBB). TWEAK did not increase MMP-9 activity or BBB permeability when injected into mice genetically deficient in the NF-κB family member p50. Furthermore, we report that inhibition of TWEAK activity during cerebral ischemia with an Fn14-Fc decoy receptor results in significant preservation of the integrity of the NVU with attenuation of cerebral ischemia-induced increase in the permeability of the BBB. We conclude that the cytokine TWEAK plays a role in the disruption of the structure and permeability of the NVU during physiological and pathological conditions.