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Immunity. 2015 Apr 21;42(4):679-91. doi: 10.1016/j.immuni.2015.03.013.

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Author information

1
Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
2
Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
3
Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
4
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
5
Department of Immunology, Weizmann Institute of Science, Rehovot Israel 76100.
6
Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
7
Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
8
Cardiovascular Research Center, Cardiovascular Division, Department of Internal Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
9
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: vladimir.litvak@umassmed.edu.
10
Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: kipnis@virginia.edu.

Abstract

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.

PMID:
25902482
PMCID:
PMC4407145
DOI:
10.1016/j.immuni.2015.03.013
[Indexed for MEDLINE]
Free PMC Article

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