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.

For many years, CD4+ effector T cells were categorized into two subsets: T helper type 1 (Th1) and type 2 (Th2) cells. More recent research has refined this model, delineating further subsets; in particular, Th17 cells, activated CD4+ T cells characterised by the production of the cytokine IL-17. Autoantigen-specific Th17 cells are associated with pathology in a number of animal models of organ-specific autoimmune disease and evidence is mounting that Th17 cells are also critical in human autoimmunity. Retinoids, a family of compounds that bind to and activate retinoic acid receptors (RARs and RXRs), are able to alter CD4+ T cell differentiation in vitro though agonism and antagonism of a range of retinoid receptors. For example, all-trans retinoic acid (ATRA) inhibits Th17 differentiation and instead promotes the upregulation of Foxp3, a key transcription factor in regulatory T cells. Importantly, treatment with retinoids can modulate Th17-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS), is ameliorated by ATRA administration due to suppression of both the differentiation and the function of Th17 cells. In this review, we discuss the unveiled molecular mechanism and the possible clinical application of retinoids for the treatment of human Th17-mediated autoimmune diseases.

Recent evidence suggests that interleukin-17-producing CD4(+) T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3(+) regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of RORgammat and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and RORgammat. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells.