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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • CpG Islands / immunology*
  • DNA Methylation
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Homeostasis / immunology
  • Humans
  • Integrases / genetics
  • Integrases / immunology
  • Longevity / immunology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / pathology
  • Male
  • Methyl-CpG-Binding Protein 2 / deficiency
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / drug effects
  • Microglia / immunology*
  • Microglia / pathology
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Rett Syndrome / genetics
  • Rett Syndrome / immunology*
  • Rett Syndrome / pathology
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Receptors, Chemokine
  • Tumor Necrosis Factor-alpha
  • Cre recombinase
  • Integrases

Associated data

  • GEO/GSE66211
  • GEO/GSE66501