Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System)
Despite a previous report on less inflammatory responses in mice with an absence of the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, using a lipopolysaccharide (LPS) injection model, proteomic analysis and cecal ligation and puncture (CLP), a sep...
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| Format: | Article |
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/10/8517 |
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| author | Pornpimol Phuengmaung Phuriwat Khiewkamrop Jiradej Makjaroen Jiraphorn Issara-Amphorn Atsadang Boonmee Salisa Benjaskulluecha Patcharee Ritprajak Aleksandra Nita-Lazar Tanapat Palaga Nattiya Hirankarn Asada Leelahavanichkul |
| author_facet | Pornpimol Phuengmaung Phuriwat Khiewkamrop Jiradej Makjaroen Jiraphorn Issara-Amphorn Atsadang Boonmee Salisa Benjaskulluecha Patcharee Ritprajak Aleksandra Nita-Lazar Tanapat Palaga Nattiya Hirankarn Asada Leelahavanichkul |
| author_sort | Pornpimol Phuengmaung |
| collection | DOAJ |
| description | Despite a previous report on less inflammatory responses in mice with an absence of the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, using a lipopolysaccharide (LPS) injection model, proteomic analysis and cecal ligation and puncture (CLP), a sepsis model that more resembles human conditions was devised. As such, analysis of cellular and secreted protein (proteome and secretome) after a single LPS activation and LPS tolerance in macrophages from Ezh2 null (Ezh2<sup>flox/flox</sup>; LysM-Cre<sup>cre/−</sup>) mice (Ezh2 null) and the littermate control mice (Ezh2<sup>fl/fl</sup>; LysM-Cre<sup>−/−</sup>) (Ezh2 control) compared with the unstimulated cells from each group indicated fewer activities in Ezh2 null macrophages, especially by the volcano plot analysis. Indeed, supernatant IL-1β and expression of genes in pro-inflammatory M1 macrophage polarization (<i>IL-1β</i> and <i>iNOS</i>), <i>TNF-α</i>, and <i>NF-κB</i> (a transcription factor) were lower in Ezh2 null macrophages compared with the control. In LPS tolerance, downregulated <i>NF-κB</i> compared with the control was also demonstrated in Ezh2 null cells. In CLP sepsis mice, those with CLP alone and CLP at 2 days after twice receiving LPS injection, representing sepsis and sepsis after endotoxemia, respectively, symptoms were less severe in Ezh2 null mice, as indicated by survival analysis and other biomarkers. However, the Ezh2 inhibitor improved survival only in CLP, but not LPS with CLP. In conclusion, an absence of Ezh2 in macrophages resulted in less severe sepsis, and the use of an Ezh2 inhibitor might be beneficial in sepsis. |
| first_indexed | 2024-03-11T03:41:00Z |
| format | Article |
| id | doaj.art-e1f9d2325df3494195d559d90963e63f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:41:00Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e1f9d2325df3494195d559d90963e63f2023-11-18T01:37:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410851710.3390/ijms24108517Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System)Pornpimol Phuengmaung0Phuriwat Khiewkamrop1Jiradej Makjaroen2Jiraphorn Issara-Amphorn3Atsadang Boonmee4Salisa Benjaskulluecha5Patcharee Ritprajak6Aleksandra Nita-Lazar7Tanapat Palaga8Nattiya Hirankarn9Asada Leelahavanichkul10Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence in Systems Biology, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandFunctional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USADepartment of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandResearch Unit in Integrative Immuno-Microbial Biochemistry and Bioresponsive Nanomaterials, Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, ThailandFunctional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USACenter of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence in Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandDespite a previous report on less inflammatory responses in mice with an absence of the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, using a lipopolysaccharide (LPS) injection model, proteomic analysis and cecal ligation and puncture (CLP), a sepsis model that more resembles human conditions was devised. As such, analysis of cellular and secreted protein (proteome and secretome) after a single LPS activation and LPS tolerance in macrophages from Ezh2 null (Ezh2<sup>flox/flox</sup>; LysM-Cre<sup>cre/−</sup>) mice (Ezh2 null) and the littermate control mice (Ezh2<sup>fl/fl</sup>; LysM-Cre<sup>−/−</sup>) (Ezh2 control) compared with the unstimulated cells from each group indicated fewer activities in Ezh2 null macrophages, especially by the volcano plot analysis. Indeed, supernatant IL-1β and expression of genes in pro-inflammatory M1 macrophage polarization (<i>IL-1β</i> and <i>iNOS</i>), <i>TNF-α</i>, and <i>NF-κB</i> (a transcription factor) were lower in Ezh2 null macrophages compared with the control. In LPS tolerance, downregulated <i>NF-κB</i> compared with the control was also demonstrated in Ezh2 null cells. In CLP sepsis mice, those with CLP alone and CLP at 2 days after twice receiving LPS injection, representing sepsis and sepsis after endotoxemia, respectively, symptoms were less severe in Ezh2 null mice, as indicated by survival analysis and other biomarkers. However, the Ezh2 inhibitor improved survival only in CLP, but not LPS with CLP. In conclusion, an absence of Ezh2 in macrophages resulted in less severe sepsis, and the use of an Ezh2 inhibitor might be beneficial in sepsis.https://www.mdpi.com/1422-0067/24/10/8517sepsislipopolysaccharidemacrophagesepigeneticsEzh2 |
| spellingShingle | Pornpimol Phuengmaung Phuriwat Khiewkamrop Jiradej Makjaroen Jiraphorn Issara-Amphorn Atsadang Boonmee Salisa Benjaskulluecha Patcharee Ritprajak Aleksandra Nita-Lazar Tanapat Palaga Nattiya Hirankarn Asada Leelahavanichkul Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System) International Journal of Molecular Sciences sepsis lipopolysaccharide macrophages epigenetics Ezh2 |
| title | Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System) |
| title_full | Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System) |
| title_fullStr | Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System) |
| title_full_unstemmed | Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System) |
| title_short | Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional <i>Ezh2</i>-Deleted Macrophages (LysM-Cre System) |
| title_sort | less severe sepsis in cecal ligation and puncture models with and without lipopolysaccharide in mice with conditional i ezh2 i deleted macrophages lysm cre system |
| topic | sepsis lipopolysaccharide macrophages epigenetics Ezh2 |
| url | https://www.mdpi.com/1422-0067/24/10/8517 |
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