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Myeloid C/EBP? deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis.

ABSTRACT: CCAAT/enhancer binding protein ? (C/EBP?) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBP? show protection against excitotoxic and ischemic CNS damage, but the involvement in this neuroprotective effect of the various C/EBP?-expressing cell types is not solved. Since C/EBP?-deficient microglia show attenuated neurotoxicity in culture, we hypothesized that specific C/EBP? deficiency in microglia could be neuroprotective in vivo. In this study, we have tested this hypothesis by generating mice with myeloid C/EBP? deficiency.Mice with myeloid C/EBP? deficiency were generated by crossing LysMCre and C/EBP?fl/fl mice. Primary microglial cultures from C/EBP?fl/fl and LysMCre-C/EBP?fl/fl mice were treated with lipopolysaccharide ± interferon ? (IFN?) for 6 h, and gene expression was analyzed by RNA sequencing. Gene expression and C/EBP? deletion were analyzed in vivo in microglia isolated from the brains of C/EBP?fl/fl and LysMCre-C/EBP?fl/fl mice treated systemically with lipolysaccharide or vehicle. Mice of LysMCre-C/EBP?fl/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.LysMCre-C/EBP?fl/fl mice showed an efficiency of C/EBP? 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/EBP? deficiency. Transcriptomic analysis of C/EBP?-deficient primary microglia revealed C/EBP?-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/EBP? deletion. CNS expression of C/EBP? was upregulated in experimental autoimmune encephalitis and in multiple sclerosis samples. Finally, LysMCre-C/EBP?fl/fl mice showed robust attenuation of clinical signs in experimental autoimmune encephalitis.This study provides new data that support a central role for C/EBP? in the biology of activated microglia, and it offers proof of concept for the therapeutic potential of microglial C/EBP? inhibition in multiple sclerosis.

PROVIDER: S-EPMC5356255 | BioStudies |

REPOSITORIES: biostudies

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