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.
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DOI：
10.4049/jimmunol.1600638
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发表时间：
2017-05-15
期刊：
影响因子：
--
通讯作者：
Krönke G
中科院分区：
文献类型：
--
作者：
Rothe T;Ipseiz N;Faas M;Lang S;Perez-Branguli F;Metzger D;Ichinose H;Winner B;Schett G;Krönke G
小胶质细胞完成关键的稳态功能，并基本上有助于中枢神经系统内的宿主防御。反过来，小胶质细胞的激活改变与神经炎症和神经退行性疾病有关。在这项研究中，我们确定核受体（NR）Nr4a1作为控制小胶质细胞激活阈值和极化的关键变阻器。在稳态小胶质细胞中，无处不在的神经元来源的应激信号，如ATP诱导表达的NR，这有助于维持一个休息和非炎症小胶质细胞表型。Nr4a1的全局和小胶质细胞特异性缺失引发了小胶质细胞的自发和压倒性激活，并导致细胞因子和NO产生增加，以及实验性自身免疫性脑脊髓炎的加速和加剧形式。配体诱导的Nr4a1激活相应地改善了这种疾病的过程。因此，我们目前的数据确定Nr4a1作为小胶质细胞活化的调节因子，并可能成为治疗炎症性CNS疾病（如多发性硬化症）的新靶点。
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.
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影响因子：
--
作者：
Goldmann T;Prinz M
通讯作者：
Prinz M
影响因子：
4.8
作者：
Krönke, G;Bochkov, VN;Leitinger, N
通讯作者：
Leitinger, N
DOI：
10.1161/atvbaha.109.191189
发表时间：
2010-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Huang W;Glass CK
通讯作者：
Glass CK
DOI：
10.1006/bbrc.2000.3169
发表时间：
2000-09-07
影响因子：
3.1
作者：
Mori, M;Gotoh, T
通讯作者：
Gotoh, T
影响因子：
15.9
作者：
Rothe, Tobias;Gruber, Florian;Kroenke, Gerhard
通讯作者：
Kroenke, Gerhard