Towards understanding the role of orphan nuclear receptor NR 4A2 in Th17 cell‐mediated central nervous system autoimmunity: An experimental approach using an animal model of multiple sclerosis

Although details of its pathogenesis remain elusive, multiple sclerosis ( MS ) is now widely accepted as an autoimmune disease of the central nervous system ( CNS ) in which autoreactive helper T cells play a pivotal role in triggering pathogenic cascades. Recently developed drugs and ongoing clinical trials clearly reflect the significance of targeting pathogenic immune cells, such as T helper 17 (Th17) cells, for MS treatment. Through comprehensive gene expression profiling analysis, we previously showed that the orphan nuclear receptor, NR 4A2, is selectively upregulated in peripheral blood T cells from relapsing–remitting MS patients. Furthermore, using experimental autoimmune encephalomyelitis, an animal model of MS , we have shown that NR 4A2 is selectively upregulated in peripheral blood T cells and T cells from inflamed CNS tissues. T cells expressing NR 4A2 in vivo were induced only when immunized with self‐peptide, not with irrelevant exogenous peptides. Accordingly, interleukin‐17 ( IL ‐17)‐producing helper T cells exclusively express NR 4A2, whether or not they secrete interferon ( IFN )‐γ, suggesting that NR 4A2‐expressing T cells represent a pathogenic Th17 subset during autoimmunity. Therefore, NR 4A2 could be a useful biomarker to estimate pathogenic Th17 cell behavior in MS patients. In addition, a blockade of NR 4A2 expression in differentiating Th17 cells with small interfering RNA not only abolished IL ‐17 secretion, but also Th17‐related genes, such as IL ‐21, c‐Maf and IL ‐23 receptor. Finally, in vivo administration of NR 4A2‐specific small interfering RNA significantly ameliorated experimental autoimmune encephalomyelitis, implying that NR 4A2 is essential for triggering MS /experimental autoimmune encephalomyelitis, and could serve as a novel therapeutic target of the diseases.