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Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons
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-i...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100394/ https://www.ncbi.nlm.nih.gov/pubmed/25093162 http://dx.doi.org/10.1155/2014/290182 |
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author | Liu, Shan Wang, Xing Li, Yun Xu, Lei Yu, Xiaoliang Ge, Lin Li, Jun Zhu, Yongjin He, Sudan |
author_facet | Liu, Shan Wang, Xing Li, Yun Xu, Lei Yu, Xiaoliang Ge, Lin Li, Jun Zhu, Yongjin He, Sudan |
author_sort | Liu, Shan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4100394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-41003942014-08-04 Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons Liu, Shan Wang, Xing Li, Yun Xu, Lei Yu, Xiaoliang Ge, Lin Li, Jun Zhu, Yongjin He, Sudan Biomed Res Int Research Article 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. Hindawi Publishing Corporation 2014 2014-07-01 /pmc/articles/PMC4100394/ /pubmed/25093162 http://dx.doi.org/10.1155/2014/290182 Text en Copyright © 2014 Shan Liu et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Liu, Shan Wang, Xing Li, Yun Xu, Lei Yu, Xiaoliang Ge, Lin Li, Jun Zhu, Yongjin He, Sudan Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons |
title | Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons |
title_full | Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons |
title_fullStr | Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons |
title_full_unstemmed | Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons |
title_short | Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons |
title_sort | necroptosis mediates tnf-induced toxicity of hippocampal neurons |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100394/ https://www.ncbi.nlm.nih.gov/pubmed/25093162 http://dx.doi.org/10.1155/2014/290182 |
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