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IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

We previously reported that astrocyte-derived proinflammatory cytokine interleukin (IL)-17A could aggravate neuronal ischemic injuries and strength autophagy both in oxygen-glucose deprivation (OGD)/reoxygenation (R)-treated neurons and peri-infarct region of mice with middle cerebral artery occlusi...

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Autores principales: Liu, Ting, Han, Song, Dai, Qingqing, Zheng, Jiayin, Liu, Cui, Li, Shujuan, Li, Junfa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933613/
https://www.ncbi.nlm.nih.gov/pubmed/31921197
http://dx.doi.org/10.3389/fimmu.2019.02952
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author Liu, Ting
Han, Song
Dai, Qingqing
Zheng, Jiayin
Liu, Cui
Li, Shujuan
Li, Junfa
author_facet Liu, Ting
Han, Song
Dai, Qingqing
Zheng, Jiayin
Liu, Cui
Li, Shujuan
Li, Junfa
author_sort Liu, Ting
collection PubMed
description We previously reported that astrocyte-derived proinflammatory cytokine interleukin (IL)-17A could aggravate neuronal ischemic injuries and strength autophagy both in oxygen-glucose deprivation (OGD)/reoxygenation (R)-treated neurons and peri-infarct region of mice with middle cerebral artery occlusion (MCAO)/reperfusion (R)-simulated ischemic stroke. In this study, the role and molecular mechanism of IL-17A in autophagy were further explored under ischemic condition. We found that exogenous addition of rmIL-17A remarkably (P < 0.001) decreased cell viability, which companying with the increases of LC3 II accumulation (P < 0.05 or 0.01) and Beclin 1 levels (P < 0.05 or 0.001), and reduction of p62 levels (P < 0.01 or 0.001) in OGD/R-treated cortical neurons (n = 6). The levels of P-mTOR (Ser 2448) (P < 0.001) and P-S6 (Ser 240/244) (P < 0.01) significantly decreased without the involvement of Akt, ERK1/2 and AMPK in cortical neurons under rmIL-17A and OGD/R treatments (n = 6). Interestingly, the co-IP analysis exhibited that PP2B and mTOR could be reciprocally immunoprecipitated; and the addition of rmIL-17A increased their interactions, PP2B activities (P < 0.001), P-Src (P < 0.001), and P-PLCγ1 (P < 0.01) levels in OGD/R-treated neurons (n = 6 or 5). The PP2B inhibitor Cyclosporin A blocked the induction of excessive autophagy (P < 0.05 or <0.001) and increased cell viability (P < 0.001) after OGD/R and rmIL-17A treatments (n = 6). In addition, the ICV injection of IL-17A neutralizing mAb could attenuate autophagy levels (P < 0.01 or 0.001, n = 6) and improve neurological functions (P < 0.01 or 0.001, n = 10) of mice after 1 h MCAO/R 24 h or 7 d. These results suggested that IL-17A-mediated excessive autophagy aggravates neuronal ischemic injuries via Src-PP2B-mTOR pathway, and IL-17A neutralization may provide a potential therapeutic effect for ischemic stroke.
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spelling pubmed-69336132020-01-09 IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway Liu, Ting Han, Song Dai, Qingqing Zheng, Jiayin Liu, Cui Li, Shujuan Li, Junfa Front Immunol Immunology We previously reported that astrocyte-derived proinflammatory cytokine interleukin (IL)-17A could aggravate neuronal ischemic injuries and strength autophagy both in oxygen-glucose deprivation (OGD)/reoxygenation (R)-treated neurons and peri-infarct region of mice with middle cerebral artery occlusion (MCAO)/reperfusion (R)-simulated ischemic stroke. In this study, the role and molecular mechanism of IL-17A in autophagy were further explored under ischemic condition. We found that exogenous addition of rmIL-17A remarkably (P < 0.001) decreased cell viability, which companying with the increases of LC3 II accumulation (P < 0.05 or 0.01) and Beclin 1 levels (P < 0.05 or 0.001), and reduction of p62 levels (P < 0.01 or 0.001) in OGD/R-treated cortical neurons (n = 6). The levels of P-mTOR (Ser 2448) (P < 0.001) and P-S6 (Ser 240/244) (P < 0.01) significantly decreased without the involvement of Akt, ERK1/2 and AMPK in cortical neurons under rmIL-17A and OGD/R treatments (n = 6). Interestingly, the co-IP analysis exhibited that PP2B and mTOR could be reciprocally immunoprecipitated; and the addition of rmIL-17A increased their interactions, PP2B activities (P < 0.001), P-Src (P < 0.001), and P-PLCγ1 (P < 0.01) levels in OGD/R-treated neurons (n = 6 or 5). The PP2B inhibitor Cyclosporin A blocked the induction of excessive autophagy (P < 0.05 or <0.001) and increased cell viability (P < 0.001) after OGD/R and rmIL-17A treatments (n = 6). In addition, the ICV injection of IL-17A neutralizing mAb could attenuate autophagy levels (P < 0.01 or 0.001, n = 6) and improve neurological functions (P < 0.01 or 0.001, n = 10) of mice after 1 h MCAO/R 24 h or 7 d. These results suggested that IL-17A-mediated excessive autophagy aggravates neuronal ischemic injuries via Src-PP2B-mTOR pathway, and IL-17A neutralization may provide a potential therapeutic effect for ischemic stroke. Frontiers Media S.A. 2019-12-20 /pmc/articles/PMC6933613/ /pubmed/31921197 http://dx.doi.org/10.3389/fimmu.2019.02952 Text en Copyright © 2019 Liu, Han, Dai, Zheng, Liu, Li and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Liu, Ting
Han, Song
Dai, Qingqing
Zheng, Jiayin
Liu, Cui
Li, Shujuan
Li, Junfa
IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway
title IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway
title_full IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway
title_fullStr IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway
title_full_unstemmed IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway
title_short IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway
title_sort il-17a-mediated excessive autophagy aggravated neuronal ischemic injuries via src-pp2b-mtor pathway
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933613/
https://www.ncbi.nlm.nih.gov/pubmed/31921197
http://dx.doi.org/10.3389/fimmu.2019.02952
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