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.

TNF-related weak inducer of apoptosis (TWEAK) levels in schizophrenia

“…Members of this superfamily have roles in many biological events including immune system development and function (Wiley and Winkles, 2003) as well as in the pathogenesis of many central nervous system diseases such as multiple sclerosis and cerebral ischemia (Feuerstein et al, 1997;Juedes et al, 2000). A relatively recently found member of this family, TNF-related weak inducer of apoptosis (TWEAK), and its receptor fibroblast growth factor-inducible 14 (Fn14) are shown to have importance both in development of pathological processess and as a target for the treatment of these diseases (Yepes, 2007).…”

“…Its expression has been detected in brain, heart, skeletal and smooth muscle, pancreas, spleen and lymphocytes (Yepes, 2007). In addition, expression of its receptor Fn14 is found to be high on most tumor cell lines of non-lymphoid origin and low on fibroblasts and endothelial and epithelial cells of healthy tissue (Burkly et al, 2011;Wajant, 2013).…”

TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic

“…TWEAK expression is more prominent in astrocytes, and Fn14 expression is found predominantly in neurons [reviewed in Ref. (35)]. Early studies using murine models of focal cerebral ischemia showed that both TWEAK and Fn14 mRNA expression in ischemic brain tissue increases within hours after an ischemic insult (36–38).…”

TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice

“…Fn14 is normally expressed at relatively low levels in healthy tissue. In the brain, Fn14 is found in endothelial cells, astrocytes, neurons, and microglia at baseline, with a further increase in expression following exposure to various inflammatory stimuli [16]. Among the main effects induced by TWEAK and Fn14 interactions are inflammation, and cell death or cell proliferation depending on the particular cell type and cytokine context [17].…”