C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis

Valente, Tony; Mancera, Pilar; Tusell, Josep Maria; Serratosa, Joan; Saura, Josep

doi:10.1016/j.neurobiolaging.2011.09.019

Cited by 27 publications

(32 citation statements)

References 69 publications

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“…A first step was to estimate the efficiency of LysMCre-induced recombination of C/EBPβ LoxP sites in microglial cells in vivo. To this end, microglia was acutely isolated by immunomagnetic separation from the whole brain of C/EBPβ fl/fl and LysMCre-C/EBPβ fl/fl adult mice treated systemically with LPS or vehicle for 16 h. At the dose and time frame used, systemic LPS induces a neuroinflammatory response with increased C/EBPβ expression in the CNS [26]. C/EBPβ protein was not detected by Western blot in microglia protein extracts from vehicle-treated mice of both genotypes.…”

Section: Resultsmentioning

confidence: 99%

Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis

Pulido-Salgado

Vidal-Taboada

Barriga

et al. 2017

J Neuroinflammation

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BackgroundCCAAT/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.MethodsMice 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.ResultsLysMCre-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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0834-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis

Pulido-Salgado

Vidal-Taboada

Barriga

et al. 2017

J Neuroinflammation

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“…CEBPB (CCAAT-enhancer binding protein beta), which is up-regulated in the CNM (Additional file 2: Figure S4), is a transcription factor known to be involved in regulating inflammatory responses. It has recently been shown to be up-regulated in AD and ALS microglia [58],[59]. CEBPB is also enriched in astrocytes, relative to neurons and oligodendrocytes [49], and has been found to be up-regulated in reactive astrocytes responding to stroke or LPS [53].…”

Section: Resultsmentioning

confidence: 99%

Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases

Burns

Morgan

et al. 2014

acta neuropathol commun

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IntroductionNeurodegenerative diseases share common pathologic features including neuroinflammation, mitochondrial dysfunction and protein aggregation, suggesting common underlying mechanisms of neurodegeneration. We undertook a meta-analysis of public gene expression data for neurodegenerative diseases to identify a common transcriptional signature of neurodegeneration.ResultsUsing 1,270 post-mortem central nervous system tissue samples from 13 patient cohorts covering four neurodegenerative diseases, we identified 243 differentially expressed genes, which were similarly dysregulated in 15 additional patient cohorts of 205 samples including seven neurodegenerative diseases. This gene signature correlated with histologic disease severity. Metallothioneins featured prominently among differentially expressed genes, and functional pathway analysis identified specific convergent themes of dysregulation. MetaCore network analyses revealed various novel candidate hub genes (e.g. STAU2). Genes associated with M1-polarized macrophages and reactive astrocytes were strongly enriched in the meta-analysis data. Evaluation of genes enriched in neurons revealed 70 down-regulated genes, over half not previously associated with neurodegeneration. Comparison with aging brain data (3 patient cohorts, 221 samples) revealed 53 of these to be unique to neurodegenerative disease, many of which are strong candidates to be important in neuropathogenesis (e.g. NDN, NAP1L2). ENCODE ChIP-seq analysis predicted common upstream transcriptional regulators not associated with normal aging (REST, RBBP5, SIN3A, SP2, YY1, ZNF143, IKZF1). Finally, we removed genes common to neurodegeneration from disease-specific gene signatures, revealing uniquely robust immune response and JAK-STAT signaling in amyotrophic lateral sclerosis.ConclusionsOur results implicate pervasive bioenergetic deficits, M1-type microglial activation and gliosis as unifying themes of neurodegeneration, and identify numerous novel genes associated with neurodegenerative processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0093-y) contains supplementary material, which is available to authorized users.

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“…Luxol fast blue method was used for staining myelin projections. Mouse sections were processed for immunohistochemistry as described previously (Valente et al, 2012). The primary and secondary antibodies used are shown in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

“…One microgram of RNA was reverse transcribed with random primers using Transcriptor Reverse Transcriptase (Roche Diagnostics Scheiwz AG, Rotkreuz, Switzerland). Then, cDNA was diluted 1/30 to perform quantitative real-time polymerase chain reaction (qRT-PCR) with IQ SYBRGREEN SuperMix (Bio-Rad Laboratories, Hercules, CA, USA) as previously described (Valente et al, 2012). The primers (Integrated DNA Technologies, Leuven, Belgium) used to amplify mouse mRNA are shown in Table 2 .…”

Section: Methodsmentioning

confidence: 99%

Alterations in CD200-CD200R1 System during EAE Already Manifest at Presymptomatic Stages

Valente

Serratosa

Perpiñá

et al. 2017

Front. Cell. Neurosci.

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In the brain of patients with multiple sclerosis, activated microglia/macrophages appear in active lesions and in normal appearing white matter. However, whether they play a beneficial or a detrimental role in the development of the pathology remains a controversial issue. The production of pro-inflammatory molecules by chronically activated microglial cells is suggested to contribute to the progression of neurodegenerative processes in neurological disease. In the healthy brain, neurons control glial activation through several inhibitory mechanisms, such as the CD200-CD200R1 interaction. Therefore, we studied whether alterations in the CD200-CD200R1 system might underlie the neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. We determined the time course of CD200 and CD200R1 expression in the brain and spinal cord of an EAE mouse model from presymptomatic to late symptomatic stages. We also assessed the correlation with associated glial activation, inflammatory response and EAE severity. Alterations in CD200 and CD200R1 expression were mainly observed in spinal cord regions in the EAE model, mostly a decrease in CD200 and an increase in CD200R1 expression. A decrease in the expression of the mRNA encoding a full CD200 protein was detected before the onset of clinical signs, and remained thereafter. A decrease in CD200 protein expression was observed from the onset of clinical signs. By contrast, CD200R1 expression increased at EAE onset, when a glial reaction associated with the production of pro- and anti-inflammatory markers occurred, and continued to be elevated during the pathology. Moreover, the magnitude of the alterations correlated with severity of the EAE mainly in spinal cord. These results suggest that neuronal-microglial communication through CD200-CD200R1 interaction is compromised in EAE. The early decreases in CD200 expression in EAE suggest that this downregulation might also occur in the initial phases of multiple sclerosis, and that this early neuronal dysfunction might facilitate the development of neuroinflammation. The increased CD200R1 expression in the EAE model highlights the potential use of targeted agonist molecules as therapeutic tools to control neuroinflammation. In summary, the CD200-CD200R1 system is a potential therapeutic target in multiple sclerosis, and CD200R1 agonists are molecules that may be worth developing in this context.

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C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis

Cited by 27 publications

References 69 publications

Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis

Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis

Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases

Alterations in CD200-CD200R1 System during EAE Already Manifest at Presymptomatic Stages

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