C/Ebpδ plays a key role in microglial activation

Abstract

Glial activation plays a central role in CNS inflammatory processes and is mediated by a selected group of transcription factors. CCAAT/enhancer binding protein δ (C/EBPδ) is a transcription factor expressed in activated glial cells that is involved in the regulation of pro-inflammatory genes. C/EBPδ is upregulated in human neurological disorders (Alzheimer’s disease, spinocerebellar ataxia type 3, ...) and in animal models (Alzheimer’s disease and experimental autoimmune encephalomyelitis). The aim of this study was to investigate whether C/EBPδ regulates gene expression in glial activation. For in vitro studies, primary mixed glial cultures were prepared from wild type and C/EBPδ -/- cortices treated with LPS+IFNγ, while in vivo studies were carried out in adult male mice from both genotypes which received systemic injection of lipolysaccharide (LPS). Moreover, C/EBPδ expression was also studied in G93A-SOD1 mice and in human samples from amyotrophic lateral sclerosis (ALS) patients. The expression of the pro-inflammatory genes NO synthase-2, cyclooxygenase-2 and interleukin (IL)-6 induced by LPS+IFNγ was attenuated in mixed glial cultures prepared from C/EBPδ -/- mice. Also, in neuron-microglia co-cultures the neurotoxicity elicited by activated microglia was abolished when C/EBPδ was absent in microglia. Systemic injection of LPS in wild type mice induced C/EBPδ expression in activated glial cells and upregulation of pro-inflammatory genes in the CNS. In C/EBPδ -/- mice, LPS-induced brain expression of NO synthase-2, tumor necrosis factor-α, IL-1β and IL-6 was attenuated. Finally, C/EBPδ was upregulated in ALS and G93A-SOD1 spinal cord where it co-localized with microglial markers. Taken together, these data show that C/EBPδ regulates pro-inflammatory gene expression in glial activation and plays an important role in microglial-induced neurotoxicity. C/EBPδ inhibition could therefore be useful in the treatment of neurodegenerative disorders with a strong neuroinflammatory component such as ALS.