Versatile Orphan Nuclear Receptor NR4A2 as a Promising Molecular Target for Multiple Sclerosis and Other Autoimmune Diseases

Abstract

The nuclear receptor family is a large group of ligand-dependent or ligand-independent transcription factors with 48 genes identified in the human genome. There is accumulating evidence that nuclear receptors are very fascinating components in terms of biological relevance to human diseases such as cancer, heart diseases, diabetes, and other lifestyle-related diseases or regulatory functions by natural and synthetic ligands. However, because of the multifunctional properties of individual nuclear receptor, the precise molecular behavior of nuclear receptors under physiological circumstances is still far from being completely understood. In addition, nuclear receptors have long been attractive drug targets and provide an enormous body of knowledge about the medicinal chemistry of their small molecule modulators. Importantly, many of the nuclear receptors are druggable targets, which is why numerous natural and synthetic nuclear receptor ligands, mostly composed of the steroid structural class, are on the market. The huge economic impact of those ligands is represented by their estimated share of 10–15% of the global pharmaceutical market. Many nuclear receptors are known as intrinsic components of immune responses including glucocorticoid receptor (GR), retinoic acid receptors (RARs), vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPARs), and retinoid orphan receptors (RORs). Herein, we discuss our recent findings that orphan nuclear receptor NR4A2 is profoundly involved in the development of autoreactive T cells and to be added to the list of beneficial molecular targets for autoimmune diseases such as multiple sclerosis.