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Cell Rep. 2019 Oct 15;29(3):697-713.e8. doi: 10.1016/j.celrep.2019.09.013.

TET2 Regulates the Neuroinflammatory Response in Microglia.

Author information

1
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.
2
Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London E1 2AT, UK.
3
Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, 171 77 Stockholm, Sweden.
4
MRC London Institute of Medical Sciences/Institute of Clinical Sciences Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
5
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
6
Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
7
Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0SP, UK.
8
Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London E1 2AT, UK. Electronic address: m.branco@qmul.ac.uk.
9
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain; Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London E1 2AT, UK. Electronic address: maburguillos@us.es.

Abstract

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.

KEYWORDS:

TET2; TLR-4; epigenetics; metabolism; microglia; neuroinflammation

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