TET2 Regulates the Neuroinflammatory Response in Microglia.

Alzheimer Disease / metabolism Amyloid / metabolism Animals Brain / metabolism DNA-Binding Proteins / antagonists & inhibitors Dioxygenases Enhancer Elements, Genetic Humans Interleukin-6 / metabolism Lipopolysaccharides / pharmacology Male Mice Mice, Inbred C57BL Mice, Knockout Microglia / cytology Nitric Oxide Synthase Type II / genetics Proto-Oncogene Proteins / antagonists & inhibitors RNA Interference RNA, Small Interfering / metabolism Rats Transcription Factor RelA / metabolism Transcription, Genetic / drug effects

TET2 TLR-4 epigenetics metabolism microglia neuroinflammation

Journal

Cell reports

ISSN: 2211-1247

Titre abrégé: Cell Rep

Pays: United States

ID NLM: 101573691

Informations de publication

Date de publication:
15 10 2019

Historique:

received: 24 10 2017

revised: 18 04 2019

accepted: 06 09 2019

entrez: 17 10 2019

pubmed: 17 10 2019

medline: 19 8 2020

Statut: ppublish

Résumé

Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid β plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

Identifiants

DOI: 10.1016/j.celrep.2019.09.013 PMID: 31618637

pubmed: 31618637

pii: S2211-1247(19)31190-8

doi: 10.1016/j.celrep.2019.09.013

pii:

doi:

Substances chimiques

Amyloid 0

DNA-Binding Proteins 0

Interleukin-6 0

Lipopolysaccharides 0

Proto-Oncogene Proteins 0

RNA, Small Interfering 0

Transcription Factor RelA 0

Dioxygenases EC 1.13.11.-

Tet2 protein, mouse EC 1.13.11.-

Nitric Oxide Synthase Type II EC 1.14.13.39

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

697-713.e8