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

James C. Cronk, Noël C. Derecki, Emily Ji, Yang Xu, Aaron E. Lampano, Igor Smirnov, Wendy Baker, Geoffrey T. Norris, Ioana Marin, Nathan Coddington, Yochai Wolf, Stephen D. Turner, Alan Aderem, Alexander L. Klibanov, Tajie H. Harris, Steffen Jung, Vladimir Litvak, Jonathan Kipnis

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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 expressionofglucocorticoid- 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 Cx3cr1creER 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.

Original languageEnglish
Pages (from-to)679-691
Number of pages13
JournalImmunity
Volume42
Issue number4
DOIs
StatePublished - Apr 21 2015
Externally publishedYes

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