Neuron-Specific Tumor Necrosis Factor Receptor–Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke. Issue 3 (September 2015)

• Record Type: Journal Article
• Authors: Gong, Jun; Li, Zuo-Zhi; Guo, Sen; Zhang, Xiao-Jing; Zhang, Peng; Zhao, Guang-Nian; Gao, Lu; Zhang, Yan; Zheng, Ankang; Zhang, Xiao-Fei; Xiang, Mei; Li, Hongliang
• Is Part Of: Hypertension. Volume 66:Issue 3(2015:Sep.)
• Publication Date: 2015-09
• Subjects: inflammation -- oxidative stress -- stroke -- TAK1 MAPKKK -- TNF receptor-associated factor 3; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.115.05430
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor–associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase–, nuclear factor κB– and Rac-1–induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-β–activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor κB, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes observed in TRAF3-overexpressing mice were completely reversed when the TRAF3–TAK1 interaction was prevented. Therefore, we have shown that TRAF3 is a central regulator of ischemic pathways, including nuclear factor κB, Rac-1, and c-Jun kinase signaling, via its interaction with and activation of TAK1. Furthermore, certain components of the TRAF3–TAK1 signaling pathway are potentially promising therapeutic targets in ischemic stroke.