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HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway
Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study a...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449914/ https://www.ncbi.nlm.nih.gov/pubmed/32863951 http://dx.doi.org/10.7150/thno.47651 |
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author | Liao, Yajin Cheng, Jinbo Kong, Xiangxi Li, Shuoshuo Li, Xiaoheng Zhang, Meijuan Zhang, He Yang, Tianli Dong, Yuan Li, Jun Xu, Yun Yuan, Zengqiang |
author_facet | Liao, Yajin Cheng, Jinbo Kong, Xiangxi Li, Shuoshuo Li, Xiaoheng Zhang, Meijuan Zhang, He Yang, Tianli Dong, Yuan Li, Jun Xu, Yun Yuan, Zengqiang |
author_sort | Liao, Yajin |
collection | PubMed |
description | Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study aimed to investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury, and to identify possible strategies for the treatment of ischemic stroke. Methods: To demonstrate that microglial histone deacetylase 3 (HDAC3) regulates the microglial cGAS-stimulator of interferon genes (cGAS-STING) pathway and is involved in I/R-induced neuroinflammation and brain injury, a series of cell biological, molecular, and biochemical approaches were utilized. These approaches include transient middle cerebral artery occlusion (tMCAO), real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, chromosome-immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), dual-luciferase reporter assay, immunohistochemistry, and confocal imaging. Results: The microglial cGAS- STING pathway was activated by mitochondrial DNA, which promoted the formation of a pro-inflammatory microenvironment. In addition, we revealed that HDAC3 transcriptionally promoted the expression of cGAS and potentiated the activation of the cGAS-STING pathway by regulating the acetylation and nuclear localization of p65 in microglia. Our in vivo results indicated that deletion of cGAS or HDAC3 in microglia attenuated I/R-induced neuroinflammation and brain injury. Conclusion: Collectively, we elucidated that the HDAC3-p65-cGAS-STING pathway is involved in the development of I/R-induced neuroinflammation, identifying a new therapeutic avenue for the treatment of ischemic stroke. |
format | Online Article Text |
id | pubmed-7449914 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-74499142020-08-27 HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway Liao, Yajin Cheng, Jinbo Kong, Xiangxi Li, Shuoshuo Li, Xiaoheng Zhang, Meijuan Zhang, He Yang, Tianli Dong, Yuan Li, Jun Xu, Yun Yuan, Zengqiang Theranostics Research Paper Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study aimed to investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury, and to identify possible strategies for the treatment of ischemic stroke. Methods: To demonstrate that microglial histone deacetylase 3 (HDAC3) regulates the microglial cGAS-stimulator of interferon genes (cGAS-STING) pathway and is involved in I/R-induced neuroinflammation and brain injury, a series of cell biological, molecular, and biochemical approaches were utilized. These approaches include transient middle cerebral artery occlusion (tMCAO), real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, chromosome-immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), dual-luciferase reporter assay, immunohistochemistry, and confocal imaging. Results: The microglial cGAS- STING pathway was activated by mitochondrial DNA, which promoted the formation of a pro-inflammatory microenvironment. In addition, we revealed that HDAC3 transcriptionally promoted the expression of cGAS and potentiated the activation of the cGAS-STING pathway by regulating the acetylation and nuclear localization of p65 in microglia. Our in vivo results indicated that deletion of cGAS or HDAC3 in microglia attenuated I/R-induced neuroinflammation and brain injury. Conclusion: Collectively, we elucidated that the HDAC3-p65-cGAS-STING pathway is involved in the development of I/R-induced neuroinflammation, identifying a new therapeutic avenue for the treatment of ischemic stroke. Ivyspring International Publisher 2020-07-29 /pmc/articles/PMC7449914/ /pubmed/32863951 http://dx.doi.org/10.7150/thno.47651 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Liao, Yajin Cheng, Jinbo Kong, Xiangxi Li, Shuoshuo Li, Xiaoheng Zhang, Meijuan Zhang, He Yang, Tianli Dong, Yuan Li, Jun Xu, Yun Yuan, Zengqiang HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway |
title | HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway |
title_full | HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway |
title_fullStr | HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway |
title_full_unstemmed | HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway |
title_short | HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway |
title_sort | hdac3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cgas-sting pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449914/ https://www.ncbi.nlm.nih.gov/pubmed/32863951 http://dx.doi.org/10.7150/thno.47651 |
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