title: Necroptosis mediates TNF-induced toxicity of hippocampal neurons.
abstract: Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Yu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ge
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Neurobiology, School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse
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