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

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

Authors :
Georg Schett
Gerhard Krönke
Tobias Rothe
Beate Winner
Daniel Metzger
Francesc Pérez-Brangulí
Hiroshi Ichinose
Maria Faas
Natacha Ipseiz
Stefanie C. Lang
University Hospital Erlangen = Uniklinikum Erlangen
Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Tokyo Institute of Technology [Tokyo] (TITECH)
univOAK, Archive ouverte
Source :
The Journal of Immunology, Journal of Immunology, Journal of Immunology, 2017, 198 (10), pp.3878-3885. ⟨10.4049/jimmunol.1600638⟩
Publication Year :
2017

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.

Details

ISSN :
00221767 and 15506606
Database :
OpenAIRE
Journal :
The Journal of Immunology
Accession number :
edsair.doi.dedup.....8313c6ff487af18beedb8f0a0aaa0668
Full Text :
https://doi.org/10.4049/jimmunol.1600638