Cargando…

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could am...

Descripción completa

Detalles Bibliográficos
Autores principales: Xia, Da-Yong, Yuan, Jin-Long, Jiang, Xiao-Chun, Qi, Min, Lai, Nian-Sheng, Wu, Ling-Yun, Zhang, Xiang-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653696/
https://www.ncbi.nlm.nih.gov/pubmed/34899720
http://dx.doi.org/10.3389/fimmu.2021.770744
_version_ 1784611718977028096
author Xia, Da-Yong
Yuan, Jin-Long
Jiang, Xiao-Chun
Qi, Min
Lai, Nian-Sheng
Wu, Ling-Yun
Zhang, Xiang-Sheng
author_facet Xia, Da-Yong
Yuan, Jin-Long
Jiang, Xiao-Chun
Qi, Min
Lai, Nian-Sheng
Wu, Ling-Yun
Zhang, Xiang-Sheng
author_sort Xia, Da-Yong
collection PubMed
description Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.
format Online
Article
Text
id pubmed-8653696
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-86536962021-12-09 SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage Xia, Da-Yong Yuan, Jin-Long Jiang, Xiao-Chun Qi, Min Lai, Nian-Sheng Wu, Ling-Yun Zhang, Xiang-Sheng Front Immunol Immunology Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling. Frontiers Media S.A. 2021-11-24 /pmc/articles/PMC8653696/ /pubmed/34899720 http://dx.doi.org/10.3389/fimmu.2021.770744 Text en Copyright © 2021 Xia, Yuan, Jiang, Qi, Lai, Wu and Zhang https://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
Xia, Da-Yong
Yuan, Jin-Long
Jiang, Xiao-Chun
Qi, Min
Lai, Nian-Sheng
Wu, Ling-Yun
Zhang, Xiang-Sheng
SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
title SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
title_full SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
title_fullStr SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
title_full_unstemmed SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
title_short SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage
title_sort sirt1 promotes m2 microglia polarization via reducing ros-mediated nlrp3 inflammasome signaling after subarachnoid hemorrhage
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653696/
https://www.ncbi.nlm.nih.gov/pubmed/34899720
http://dx.doi.org/10.3389/fimmu.2021.770744
work_keys_str_mv AT xiadayong sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage
AT yuanjinlong sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage
AT jiangxiaochun sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage
AT qimin sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage
AT lainiansheng sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage
AT wulingyun sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage
AT zhangxiangsheng sirt1promotesm2microgliapolarizationviareducingrosmediatednlrp3inflammasomesignalingaftersubarachnoidhemorrhage