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N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice
Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccha...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979126/ https://www.ncbi.nlm.nih.gov/pubmed/36864027 http://dx.doi.org/10.1038/s41467-023-36865-7 |
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author | Wang, Xiangyu Ding, Yan Li, Ran Zhang, Rujun Ge, Xuejun Gao, Ruifang Wang, Miao Huang, Yubing Zhang, Fang Zhao, Bin Liao, Wang Du, Jie |
author_facet | Wang, Xiangyu Ding, Yan Li, Ran Zhang, Rujun Ge, Xuejun Gao, Ruifang Wang, Miao Huang, Yubing Zhang, Fang Zhao, Bin Liao, Wang Du, Jie |
author_sort | Wang, Xiangyu |
collection | PubMed |
description | Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages reduces the production of pro-inflammatory cytokines and myocardial impairment. In addition, exposure to LPS upregulates the lysine acetyltransferase, KAT2B, to promote METTL14 protein stability through acetylation at K398, leading to the increased m(6)A methylation of Spi2a in macrophages. m(6)A-methylated Spi2a directly binds to IKKβ to impair IKK complex formation and inactivate the NF-κB pathway. The loss of m(6)A methylation in macrophages aggravates cytokine production and myocardial damage in mice under septic conditions, whereas forced expression of Spi2a reverses this phenotype. In septic patients, the mRNA expression levels of the human orthologue SERPINA3 negatively correlates with those of the cytokines, TNF, IL-6, IL-1β and IFNγ. Altogether, these findings suggest that m(6)A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis. |
format | Online Article Text |
id | pubmed-9979126 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99791262023-03-02 N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice Wang, Xiangyu Ding, Yan Li, Ran Zhang, Rujun Ge, Xuejun Gao, Ruifang Wang, Miao Huang, Yubing Zhang, Fang Zhao, Bin Liao, Wang Du, Jie Nat Commun Article Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages reduces the production of pro-inflammatory cytokines and myocardial impairment. In addition, exposure to LPS upregulates the lysine acetyltransferase, KAT2B, to promote METTL14 protein stability through acetylation at K398, leading to the increased m(6)A methylation of Spi2a in macrophages. m(6)A-methylated Spi2a directly binds to IKKβ to impair IKK complex formation and inactivate the NF-κB pathway. The loss of m(6)A methylation in macrophages aggravates cytokine production and myocardial damage in mice under septic conditions, whereas forced expression of Spi2a reverses this phenotype. In septic patients, the mRNA expression levels of the human orthologue SERPINA3 negatively correlates with those of the cytokines, TNF, IL-6, IL-1β and IFNγ. Altogether, these findings suggest that m(6)A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis. Nature Publishing Group UK 2023-03-02 /pmc/articles/PMC9979126/ /pubmed/36864027 http://dx.doi.org/10.1038/s41467-023-36865-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wang, Xiangyu Ding, Yan Li, Ran Zhang, Rujun Ge, Xuejun Gao, Ruifang Wang, Miao Huang, Yubing Zhang, Fang Zhao, Bin Liao, Wang Du, Jie N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
title | N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
title_full | N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
title_fullStr | N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
title_full_unstemmed | N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
title_short | N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
title_sort | n(6)-methyladenosine of spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979126/ https://www.ncbi.nlm.nih.gov/pubmed/36864027 http://dx.doi.org/10.1038/s41467-023-36865-7 |
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