TWEAK—Fn14 Pathway Inhibition Protects the Integrity of the Neurovascular Unit during Cerebral Ischemia

Abstract

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.

Inflammation in the CNS: Advancing the Field Using Intravital Imaging

“…and Cu + , capable of generating further radical formation in Fenton-like reactions; (3) o-semiaminoquinone readily reacts with oxygen generating quinone-imine, another highly reactive product which also participates in additional oxidative reactions (113). In line with this, 3-HK and 3-HAA (10 μM) induced neuronal cell death with apoptotic features following generation of ROS in primary striatal neurons.…”

“…This characterization has been performed in vitro at concentrations that are supraphysiological, ranging from 10 μM to 1 mM. These concentrations are considerably higher than both normal brain (~0.08-0.3 μM) and pathological brain (0.3-1.2 μM) concentrations and could evoke toxicity not observed under normal conditions (113). In support of this, there is growing evidence suggesting that 3-HK is an endogenous antioxidant.…”

“…During inflammation, the CNS interstitial ECM as well as the perineuronal nets undergo substantial remodeling (113). Factors produced by infiltrating immune cells and resident glial cells drive this inflammatory restructuring.…”

“…Therefore, IDO-1 competent dendritic cells also contribute to KP-mediated immune-suppression by contributing to a tolerogenic environment. Together, this plays a substantial role in the development of immune tolerance and the induction of a negative feedback loop that regulates the immune response (113).…”

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

“…Nevertheless, it appears that the TWEAK-Fn14 system is active in processes related to growth and remodeling of tissue and organs during development and tissue repair. In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6,7), regulation of muscle development and muscle regeneration (8)(9)(10)(11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus erythematosus-related nephritis (13), 2,4,6-trinitrobenzene sulfonic acid-induced colitis (14), renal and cerebral ischemia (15)(16)(17)(18), and collagen-induced arthritis (19,20).…”