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RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex

Cell death and subsequent inflammation are 2 key pathological changes occurring in cerebral ischemia. Active microglia/macrophages play a double-edged role depending on the balance of their M1/M2 phenotypes. Necrosis is the predominant type of cell death following ischemia. However, how necrotic cel...

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Autores principales: Yang, Jiping, Zhao, Youyi, Zhang, Li, Fan, Hong, Qi, Chuchu, Zhang, Kun, Liu, Xinyu, Fei, Lin, Chen, Siwei, Wang, Mengmeng, Kuang, Fang, Wang, Yazhou, Wu, Shengxi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998990/
https://www.ncbi.nlm.nih.gov/pubmed/29746630
http://dx.doi.org/10.1093/cercor/bhy089
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author Yang, Jiping
Zhao, Youyi
Zhang, Li
Fan, Hong
Qi, Chuchu
Zhang, Kun
Liu, Xinyu
Fei, Lin
Chen, Siwei
Wang, Mengmeng
Kuang, Fang
Wang, Yazhou
Wu, Shengxi
author_facet Yang, Jiping
Zhao, Youyi
Zhang, Li
Fan, Hong
Qi, Chuchu
Zhang, Kun
Liu, Xinyu
Fei, Lin
Chen, Siwei
Wang, Mengmeng
Kuang, Fang
Wang, Yazhou
Wu, Shengxi
author_sort Yang, Jiping
collection PubMed
description Cell death and subsequent inflammation are 2 key pathological changes occurring in cerebral ischemia. Active microglia/macrophages play a double-edged role depending on the balance of their M1/M2 phenotypes. Necrosis is the predominant type of cell death following ischemia. However, how necrotic cells modulate the M1/M2 polarization of microglia/macrophages remains poorly investigated. Here, we reported that ischemia induces a rapid RIPK3/MLKL-mediated neuron-dominated necroptosis, a type of programmed necrosis. Ablating RIPK3 or MLKL could switch the activation of microglia/macrophages from M1 to the M2 type in the ischemic cortex. Conditioned medium of oxygen-glucose deprivation (OGD)-treated wild-type (WT) neurons induced M1 polarization, while that of RIPK3(−/−) neurons favored M2 polarization. OGD treatment induces proinflammatory IL-18 and TNFα in WT but not in RIPK3(−/−) neurons, which in turn upregulate anti-inflammatory IL-4 and IL-10. Furthermore, the expression of Myd88—a common downstream adaptor of toll-like receptors—is significantly upregulated in the microglia/macrophages of ischemic WT but not of RIPK3(−/−) or MLKL(−/−) cortices. Antagonizing the function of Myd88 could phenocopy the effects of RIPK3/MLKL-knockout on the polarization of microglia/macrophages and was neuroprotective. Our data revealed a novel role of necroptotic neurons in modulating the M1/M2 balance of microglia/macrophages in the ischemic cortex, possibly through Myd88 signaling.
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spelling pubmed-59989902018-06-18 RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex Yang, Jiping Zhao, Youyi Zhang, Li Fan, Hong Qi, Chuchu Zhang, Kun Liu, Xinyu Fei, Lin Chen, Siwei Wang, Mengmeng Kuang, Fang Wang, Yazhou Wu, Shengxi Cereb Cortex Original Articles Cell death and subsequent inflammation are 2 key pathological changes occurring in cerebral ischemia. Active microglia/macrophages play a double-edged role depending on the balance of their M1/M2 phenotypes. Necrosis is the predominant type of cell death following ischemia. However, how necrotic cells modulate the M1/M2 polarization of microglia/macrophages remains poorly investigated. Here, we reported that ischemia induces a rapid RIPK3/MLKL-mediated neuron-dominated necroptosis, a type of programmed necrosis. Ablating RIPK3 or MLKL could switch the activation of microglia/macrophages from M1 to the M2 type in the ischemic cortex. Conditioned medium of oxygen-glucose deprivation (OGD)-treated wild-type (WT) neurons induced M1 polarization, while that of RIPK3(−/−) neurons favored M2 polarization. OGD treatment induces proinflammatory IL-18 and TNFα in WT but not in RIPK3(−/−) neurons, which in turn upregulate anti-inflammatory IL-4 and IL-10. Furthermore, the expression of Myd88—a common downstream adaptor of toll-like receptors—is significantly upregulated in the microglia/macrophages of ischemic WT but not of RIPK3(−/−) or MLKL(−/−) cortices. Antagonizing the function of Myd88 could phenocopy the effects of RIPK3/MLKL-knockout on the polarization of microglia/macrophages and was neuroprotective. Our data revealed a novel role of necroptotic neurons in modulating the M1/M2 balance of microglia/macrophages in the ischemic cortex, possibly through Myd88 signaling. Oxford University Press 2018-07 2018-05-09 /pmc/articles/PMC5998990/ /pubmed/29746630 http://dx.doi.org/10.1093/cercor/bhy089 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Yang, Jiping
Zhao, Youyi
Zhang, Li
Fan, Hong
Qi, Chuchu
Zhang, Kun
Liu, Xinyu
Fei, Lin
Chen, Siwei
Wang, Mengmeng
Kuang, Fang
Wang, Yazhou
Wu, Shengxi
RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex
title RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex
title_full RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex
title_fullStr RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex
title_full_unstemmed RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex
title_short RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex
title_sort ripk3/mlkl-mediated neuronal necroptosis modulates the m1/m2 polarization of microglia/macrophages in the ischemic cortex
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998990/
https://www.ncbi.nlm.nih.gov/pubmed/29746630
http://dx.doi.org/10.1093/cercor/bhy089
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