Action of RORs and their ligands in (patho)physiology

Abstract

The retinoic-acid-receptor-related orphan receptors (RORs) are members of the nuclear receptor (NR) superfamily whose activity has been implicated in several physiological and pathological processes. The RORs, specifically RORα and RORγ, are considered to be master regulators of T(H)17 cells, a recently described subset of CD4(+) T helper cells that have been demonstrated to have a pathological role in autoimmune disease. As with most members of the NR superfamily, RORs are ligand-regulated, suggesting that their activity can be modulated by synthetic ligands. Recent advances in the field have established that selective inhibition of the RORs is a viable therapeutic approach for not only the treatment of autoimmune disorders but also ROR-mediated metabolic disorders.

Figure 1. ROR Regulation of the Circadian Rhythm

Circadian rhythms are biological processes that display endogenous oscillations of approximately 24 hours and are regulated by a core circadian clock. The master circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. There are several interconnected transcriptional auto-regulatory feedback loops controlling the circadian cycle. Heterodimers of BMAL1 and CLOCK activate the expression of CRY and PER genes. Once the CRY/PER heterodimers reaches a critical threshold, they enter the nucleus and repress BMAL/CLOCK transactivation. RORα and REV-ERBα have been demonstrated to positively or negatively regulate the expression of BMAL1, respectively. RORα competes with REV-ERBa for binding of their shared DNA response element in the BMAL1 promoter. The oscillating pattern of RORα and REVERBα in the SCN dictates the circadian pattern of of BMAL1 expression. This RORα/REV-ERBα feedback loops interconnects the positive and negative arms of the core circadian clock.

Figure 2. RORα and RORγ in T_H17 Cell Differentiation

In the presence of several exogenous factors, including TGFβ, IL-6, and IL-1, naïve CD4⁺ T cells differentiate into T_H17 cells. Exogenous IL-23 is necessary for the propagation of pathogenic T_H17 cells. The expression of RORα and particularly RORγt is necessary for T_H17 cell differentiation and for the expression of IL-17A and IL-17F, among other cytokines. T_H17 cells play a significant role in host defense against extracellular pathogens at mucosal surfaces. However, aberrant T_H17 cell activity has been associated with the pathology of several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and psoriasis.

Figure 3. Regulation of ROR activity with synthetic ligands

The RORs are considered to have intrinsic transcriptional activity, meaning that they are constitutively active and bind coactivators in the absence of ligand. However, due to the ubiquitous expression of putative ROR ligands, it remains to be determined whether the RORs are ever in an unbound state or require ligand for receptor stability. Treatment with an agonist(SR1078) would result in the recruitment of more coactivator proteins, thereby enhancing transcriptional activity. Inverse agonists, when bound to the RORs LBD, induce a conformational change in the receptor resulting in dissociation of coactivator proteins and recruitment of corepressor proteins. Inverse agonists repress the activity of the receptors.