Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily (TNFSF) that acts on responsive cells via binding to a cell surface receptor known as fibroblast growth factor-inducible 14 (Fn14). TWEAK and Fn14 expression has been detected under non-ischemic conditions in neurons, and either middle cerebral artery occlusion (MCAO) or exposure of neuronal cultures to oxygen-glucose deprivation (OGD) conditions results in a significant increase in the expression of this cytokine and its receptor. We have demonstrated that the binding of TWEAK to Fn14 induces NF-?B activation and neuronal cell death and that inhibition of TWEAK activity following MCAO either by treatment with a soluble Fn14-Fc decoy receptor or genetic deficiency of Fn14 decreases the volume of the ischemic lesion and protects the area of ischemia penumbra. In this proposal we hypothesize that the interaction between TWEAK and Fn14 during cerebral ischemia induces neuronal cell death in the area of ischemic penumbra via caspase- dependent and -independent mechanisms. More specifically, we postulate that the binding of TWEAK to Fn14 following MCAO induces cell death by activation of the "intrinsic" and "extrinsic" apoptotic pathways, as well as by NF-?B-dependent activation of poly(ADP-ribose) polymerase-1 (PARP-1) with nuclear translocation of the apoptosis-inducing factor (AIF). Moreover, treatment with inhibitors of TWEAK activity after MCAO decreases cerebral ischemia-induced neuronal death and improves the fate of the ischemic tissue as evaluated by in vivo state-of-the-art neuroimaging techniques. These are clinically-relevant studies likely to result in a new therapeutic approach to prevent neuronal cell death in patients with ischemic stroke.
Early after the onset of ischemic stroke there is an increase in the expression of the cytokine TWEAK and its receptor Fn14. The binding of TWEAK to Fn14 induces neuronal death. This application focuses on the study of the mechanism whereby TWEAK induces cell death and the use of inhibitors of TWEAK activity as a potential therapeutic strategy to prevent neuronal death during acute ischemic stroke.
|Wu, Fang; Catano, Marcela; Echeverry, Ramiro et al. (2014) Urokinase-type plasminogen activator promotes dendritic spine recovery and improves neurological outcome following ischemic stroke. J Neurosci 34:14219-32|
|An, J; Haile, W B; Wu, F et al. (2014) Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system. Neuroscience 257:41-8|
|Wu, Fang; Echeverry, Ramiro; Wu, Jialing et al. (2013) Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK1/2-CREB-ATF3 signaling pathway. Mol Cell Neurosci 52:9-19|
|Echeverry, Ramiro; Wu, Fang; Haile, Woldeab B et al. (2012) The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system. J Neuroinflammation 9:45|
|Haile, Woldeab B; Wu, Jialing; Echeverry, Ramiro et al. (2012) Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-ýý. J Cereb Blood Flow Metab 32:57-69|
|Wu, Jialing; Echeverry, Ramiro; Guzman, Johanna et al. (2010) Neuroserpin protects neurons from ischemia-induced plasmin-mediated cell death independently of tissue-type plasminogen activator inhibition. Am J Pathol 177:2576-84|
|Echeverry, Ramiro; Wu, Jialing; Haile, Woldeab B et al. (2010) Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus. J Clin Invest 120:2194-205|
|Haile, Woldeab B; Echeverry, Ramiro; Wu, Jialing et al. (2010) The interaction between tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 promotes the recruitment of neutrophils into the ischemic brain. J Cereb Blood Flow Metab 30:1147-56|
|Haile, W B; Echeverry, R; Wu, F et al. (2010) Tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 mediate cerebral ischemia-induced poly(ADP-ribose) polymerase-1 activation and neuronal death. Neuroscience 171:1256-64|