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J Immunol. 2017 May 15;198(10):3878-3885. doi: 10.4049/jimmunol.1600638. Epub 2017 Apr 14.

The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation.

Author information

1
Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, 91054 Erlangen, Germany.
2
Nikolaus Fiebiger Center of Molecular Medicine, University of Erlangen, 91054 Erlangen, Germany.
3
IZKF Junior Research Group III and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, University Hospital Erlangen, 91054 Erlangen, Germany.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964, Université de Strasbourg, 67400 Illkirch, France; and.
5
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
6
Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, 91054 Erlangen, Germany; gerhard.kroenke@uk-erlangen.de.

Abstract

Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO production as well as in an accelerated and exacerbated form of experimental autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.

PMID:
28411187
PMCID:
PMC5798579
DOI:
10.4049/jimmunol.1600638
[Indexed for MEDLINE]
Free PMC Article

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