TWEAK and the central nervous system

Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily that acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro and in vivo. Recent studies have indicated that TWEAK and Fn14 are expressed in the central nervous system (CNS), and that in response to a variety of stimuli, including cerebral ischemia, there is an increase in TWEAK and Fn14 expression in perivascular astrocytes, microglia, endothelial cells, and neurons with subsequent increase in the permeability of the blood-brain barrier (BBB) and cell death. Furthermore, there is a growing body of evidence indicating that TWEAK induces the activation of the NF-kappaB in the CNS with release of proinflammatory cytokines and matrix metalloproteinases. In addition, inhibition of TWEAK activity by either treatment with a Fn14-Fc fusion protein or neutralizing anti-TWEAK antibodies has shown therapeutic efficacy in animal models of ischemic stroke, cerebral edema, and multiple sclerosis.