The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation.
Fiche publication
Date publication
avril 2017
Journal
Journal of immunology (Baltimore, Md. : 1950)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel
Tous les auteurs :
Rothe T, Ipseiz N, Faas M, Lang S, Perez-Branguli F, Metzger D, Ichinose H, Winner B, Schett G, Krönke G
Lien Pubmed
Résumé
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.
Mots clés
Adenosine Triphosphate, pharmacology, Animals, Cells, Cultured, Central Nervous System, immunology, Central Nervous System Diseases, therapy, Cytokines, biosynthesis, Encephalomyelitis, Autoimmune, Experimental, immunology, Gene Expression Regulation, Humans, Inflammation, Macrophage Activation, Mice, Mice, Inbred C57BL, Microglia, drug effects, Multiple Sclerosis, therapy, Neurodegenerative Diseases, therapy, Nitric Oxide, biosynthesis, Nuclear Receptor Subfamily 4, Group A, Member 1, deficiency
Référence
J. Immunol.. 2017 Apr;: