Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis
Background CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBPβ show protection against excitotoxic and ischemic CNS damage, but the involvement in this neuroprotective effect of...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/108976 |
| Acceso en línea: | https://hdl.handle.net/2445/108976 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties neurodegeneratives Encefalomielitis Genètica mèdica Inflamació RNA Neurodegenerative Diseases Encephalomyelitis Medical genetics Inflammation |
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Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitisPulido Salgado, MartaVidal Taboada, José ManuelGarcía-Díaz Barriga, GerardoSerratosa i Serdà, JoanValente, TonyCastillo, PaolaMatalonga, JonathanStraccia, MarcoCanals i Coll, Josep M.Valledor Fernández, AnnabelSolà i Subirana, CarmeSaura Martí, JosepMalalties neurodegenerativesEncefalomielitisGenètica mèdicaInflamacióRNANeurodegenerative DiseasesEncephalomyelitisMedical geneticsInflammationRNABackground CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBPβ show protection against excitotoxic and ischemic CNS damage, but the involvement in this neuroprotective effect of the various C/EBPβ-expressing cell types is not solved. Since C/EBPβ-deficient microglia show attenuated neurotoxicity in culture, we hypothesized that specific C/EBPβ deficiency in microglia could be neuroprotective in vivo. In this study, we have tested this hypothesis by generating mice with myeloid C/EBPβ deficiency. Methods Mice with myeloid C/EBPβ deficiency were generated by crossing LysMCre and C/EBPβfl/fl mice. Primary microglial cultures from C/EBPβfl/fl and LysMCre-C/EBPβfl/fl mice were treated with lipopolysaccharide ± interferon γ (IFNγ) for 6 h, and gene expression was analyzed by RNA sequencing. Gene expression and C/EBPβ deletion were analyzed in vivo in microglia isolated from the brains of C/EBPβfl/fl and LysMCre-C/EBPβfl/fl mice treated systemically with lipolysaccharide or vehicle. Mice of LysMCre-C/EBPβfl/fl or control genotypes were subjected to experimental autoimmune encephalitis and analyzed for clinical signs for 52 days. One- or two-way ANOVA or Kruskal-Wallis with their appropriate post hoc tests were used. Results LysMCre-C/EBPβfl/fl mice showed an efficiency of C/EBPβ deletion in microglia of 100 and 90% in vitro and in vivo, respectively. These mice were devoid of female infertility, perinatal mortality and reduced lifespan that are associated to full C/EBPβ deficiency. Transcriptomic analysis of C/EBPβ-deficient primary microglia revealed C/EBPβ-dependent expression of 1068 genes, significantly enriched in inflammatory and innate immune responses GO terms. In vivo, microglial expression of the pro-inflammatory genes Cybb, Ptges, Il23a, Tnf and Csf3 induced by systemic lipopolysaccharide injection was also blunted by C/EBPβ deletion. CNS expression of C/EBPβ was upregulated in experimental autoimmune encephalitis and in multiple sclerosis samples. Finally, LysMCre-C/EBPβfl/fl mice showed robust attenuation of clinical signs in experimental autoimmune encephalitis. Conclusion This study provides new data that support a central role for C/EBPβ in the biology of activated microglia, and it offers proof of concept for the therapeutic potential of microglial C/EBPβ inhibition in multiple sclerosis.BioMed Central2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/108976Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s12974-017-0834-5Journal of Neuroinflammation, 2017, vol. 14, num. 54https://doi.org/10.1186/s12974-017-0834-5cc-by (c) Pulido Salgado et al., 2017http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1089762026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| title |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| spellingShingle |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis Pulido Salgado, Marta Malalties neurodegeneratives Encefalomielitis Genètica mèdica Inflamació RNA Neurodegenerative Diseases Encephalomyelitis Medical genetics Inflammation RNA |
| title_short |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| title_full |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| title_fullStr |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| title_full_unstemmed |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| title_sort |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
| dc.creator.none.fl_str_mv |
Pulido Salgado, Marta Vidal Taboada, José Manuel García-Díaz Barriga, Gerardo Serratosa i Serdà, Joan Valente, Tony Castillo, Paola Matalonga, Jonathan Straccia, Marco Canals i Coll, Josep M. Valledor Fernández, Annabel Solà i Subirana, Carme Saura Martí, Josep |
| author |
Pulido Salgado, Marta |
| author_facet |
Pulido Salgado, Marta Vidal Taboada, José Manuel García-Díaz Barriga, Gerardo Serratosa i Serdà, Joan Valente, Tony Castillo, Paola Matalonga, Jonathan Straccia, Marco Canals i Coll, Josep M. Valledor Fernández, Annabel Solà i Subirana, Carme Saura Martí, Josep |
| author_role |
author |
| author2 |
Vidal Taboada, José Manuel García-Díaz Barriga, Gerardo Serratosa i Serdà, Joan Valente, Tony Castillo, Paola Matalonga, Jonathan Straccia, Marco Canals i Coll, Josep M. Valledor Fernández, Annabel Solà i Subirana, Carme Saura Martí, Josep |
| author2_role |
author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malalties neurodegeneratives Encefalomielitis Genètica mèdica Inflamació RNA Neurodegenerative Diseases Encephalomyelitis Medical genetics Inflammation RNA |
| topic |
Malalties neurodegeneratives Encefalomielitis Genètica mèdica Inflamació RNA Neurodegenerative Diseases Encephalomyelitis Medical genetics Inflammation RNA |
| description |
Background CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBPβ show protection against excitotoxic and ischemic CNS damage, but the involvement in this neuroprotective effect of the various C/EBPβ-expressing cell types is not solved. Since C/EBPβ-deficient microglia show attenuated neurotoxicity in culture, we hypothesized that specific C/EBPβ deficiency in microglia could be neuroprotective in vivo. In this study, we have tested this hypothesis by generating mice with myeloid C/EBPβ deficiency. Methods Mice with myeloid C/EBPβ deficiency were generated by crossing LysMCre and C/EBPβfl/fl mice. Primary microglial cultures from C/EBPβfl/fl and LysMCre-C/EBPβfl/fl mice were treated with lipopolysaccharide ± interferon γ (IFNγ) for 6 h, and gene expression was analyzed by RNA sequencing. Gene expression and C/EBPβ deletion were analyzed in vivo in microglia isolated from the brains of C/EBPβfl/fl and LysMCre-C/EBPβfl/fl mice treated systemically with lipolysaccharide or vehicle. Mice of LysMCre-C/EBPβfl/fl or control genotypes were subjected to experimental autoimmune encephalitis and analyzed for clinical signs for 52 days. One- or two-way ANOVA or Kruskal-Wallis with their appropriate post hoc tests were used. Results LysMCre-C/EBPβfl/fl mice showed an efficiency of C/EBPβ deletion in microglia of 100 and 90% in vitro and in vivo, respectively. These mice were devoid of female infertility, perinatal mortality and reduced lifespan that are associated to full C/EBPβ deficiency. Transcriptomic analysis of C/EBPβ-deficient primary microglia revealed C/EBPβ-dependent expression of 1068 genes, significantly enriched in inflammatory and innate immune responses GO terms. In vivo, microglial expression of the pro-inflammatory genes Cybb, Ptges, Il23a, Tnf and Csf3 induced by systemic lipopolysaccharide injection was also blunted by C/EBPβ deletion. CNS expression of C/EBPβ was upregulated in experimental autoimmune encephalitis and in multiple sclerosis samples. Finally, LysMCre-C/EBPβfl/fl mice showed robust attenuation of clinical signs in experimental autoimmune encephalitis. Conclusion This study provides new data that support a central role for C/EBPβ in the biology of activated microglia, and it offers proof of concept for the therapeutic potential of microglial C/EBPβ inhibition in multiple sclerosis. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/108976 |
| url |
https://hdl.handle.net/2445/108976 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
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Reproducció del document publicat a: https://doi.org/10.1186/s12974-017-0834-5 Journal of Neuroinflammation, 2017, vol. 14, num. 54 https://doi.org/10.1186/s12974-017-0834-5 |
| dc.rights.none.fl_str_mv |
cc-by (c) Pulido Salgado et al., 2017 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess |
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cc-by (c) Pulido Salgado et al., 2017 http://creativecommons.org/licenses/by/3.0/es |
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openAccess |
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application/pdf |
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BioMed Central |
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BioMed Central |
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Articles publicats en revistes (Biomedicina) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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