dc.contributor |
Universitat de Barcelona |
dc.contributor.author |
Pulido Salgado, Marta |
dc.contributor.author |
Vidal Taboada, José Manuel |
dc.contributor.author |
Garcia Diaz-Barriga, Gerardo |
dc.contributor.author |
Serratosa i Serdà, Joan |
dc.contributor.author |
Valente, Tony |
dc.contributor.author |
Castillo, Paola |
dc.contributor.author |
Matalonga, Jonathan |
dc.contributor.author |
Straccia, Marco |
dc.contributor.author |
Canals i Coll, Josep M. |
dc.contributor.author |
Valledor Fernández, Annabel |
dc.contributor.author |
Solà i Subirana, Carme |
dc.contributor.author |
Saura Martí, Josep |
dc.date |
2017-03-27T14:54:40Z |
dc.date |
2017-03-27T14:54:40Z |
dc.date |
2017-03-16 |
dc.date |
2017-03-27T14:54:40Z |
dc.identifier.citation |
1742-2094 |
dc.identifier.citation |
670527 |
dc.identifier.uri |
http://hdl.handle.net/2445/108976 |
dc.format |
20 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
BioMed Central |
dc.relation |
Reproducció del document publicat a: https://doi.org/10.1186/s12974-017-0834-5 |
dc.relation |
Journal of Neuroinflammation, 2017, vol. 14, num. 54 |
dc.relation |
https://doi.org/10.1186/s12974-017-0834-5 |
dc.rights |
cc-by (c) Pulido Salgado et al., 2017 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.rights |
http://creativecommons.org/licenses/by/3.0/es |
dc.subject |
Malalties neurodegeneratives |
dc.subject |
Encefalomielitis |
dc.subject |
Genètica mèdica |
dc.subject |
Inflamació |
dc.subject |
RNA |
dc.subject |
Neurodegenerative diseases |
dc.subject |
Encephalomyelitis |
dc.subject |
Medical genetics |
dc.subject |
Inflammation |
dc.subject |
RNA |
dc.title |
Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/publishedVersion |
dc.description.abstract |
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. |