Dataset Information

CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells.

ABSTRACT: The CCAAT/enhancer binding protein delta (CEBPD, C/EBP?, NF-IL6?) is induced in many inflammation-related diseases, suggesting that CEBPD and its downstream targets may play central roles in these conditions. Neuropathological studies show that a neuroinflammatory response parallels the early stages of Alzheimer's disease (AD). However, the precise mechanistic correlation between inflammation and AD pathogenesis remains unclear. CEBPD is upregulated in the astrocytes of AD patients. Therefore, we asked if activation of astrocytic CEBPD could contribute to AD pathogenesis. In this report, a novel role of CEBPD in attenuating macrophage-mediated phagocytosis of damaged neuron cells was found. By global gene expression profiling, we identified the inflammatory marker pentraxin-3 (PTX3, TNFAIP5, TSG-14) as a CEBPD target in astrocytes. Furthermore, we demonstrate that PTX3 participates in the attenuation of macrophage-mediated phagocytosis of damaged neuron cells. This study provides the first demonstration of a role for astrocytic CEBPD and the CEBPD-regulated molecule PTX3 in the accumulation of damaged neurons, which is a hallmark of AD pathogenesis.

SUBMITTER: Ko CY

PROVIDER: S-EPMC6309870 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells.

Ko Chiung-Yuan CY Chang Ling-Hua LH Lee Yi-Chao YC Sterneck Esta E Cheng Chun-Pei CP Chen Shun-Hua SH Huang A-Mei AM Tseng Joseph T JT Wang Ju-Ming JM

Neurobiology of aging 20101126 2

The CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ, NF-IL6β) is induced in many inflammation-related diseases, suggesting that CEBPD and its downstream targets may play central roles in these conditions. Neuropathological studies show that a neuroinflammatory response parallels the early stages of Alzheimer's disease (AD). However, the precise mechanistic correlation between inflammation and AD pathogenesis remains unclear. CEBPD is upregulated in the astrocytes of AD patients. Therefore, w ...[more]

PMID: 21112127

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Project description:α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

Dataset Information

CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells.

Publications

CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells.

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