Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

Abstract

In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs). We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated.

Keywords: RORα; RORβ; RORγ; Th17 cells; agonists; antagonist; autism; autoimmune disease; brain; cancer; cholesterol biosynthesis; circadian clock; diabetes; glucose homeostasis; immunity; innate lymphoid cells; insulin sensitivity; lipid metabolism; metabolism; retina; retinoic acid-related orphan receptor; transcription.

Figure 1. Multiple functions of RORs in lymphocyte development

A. Roles of RORγt in the development of Th17 cells, γδ-17 T cells, lymphoid tissue inducer (LTi) cells and innate lymphoid cells 3 (ILC3) cells. (B) Role of RORα in the development of ILC2 cells. RORα has also a role in the regulation of Th17 cells.

Figure 2. RORγt-dependent induction of Th17 differentiation and Th17-associated genes

In Th0 cells, IRF4 and BATF are bound to chromatin near Th17-associated genes, but the loci are transcriptionally silent. Upon exposure to cytokines, such as IL-6, STAT-3 becomes phosphorylated and transfers to the nucleus, where it binds DNA near IRF4 and BATF and induces Rorc transcription. RORγt can then join the IRF4/BATF/STAT3 transcription factor complex and induce expression of Th17-associated genes, such as Il17 and Il23r.

Figure 3. RORα and RORγ function as intermediaries between the circadian clock and its regulation of glucose/lipid metabolic and inflammatory gene expression

RORs are linked to the circadian clock at different levels: a) ROR expression is regulated by the circadian clock machinery, including Bmal1, Clock, Rev-Erbs and Cry1; b) RORs are involved in the modulation of clock gene expression, including Npas2, Clock and Rev-Erb, and participate in the regulation of the rhythmic expression of glucose and lipid metabolic genes as well as inflammatory genes; c) Deficiency in RORα or RORβ causes changes in the circadian behavior, which might be linked to neuropsychiatric disorders, while deficiency in RORγ leads to increased insulin sensitivity and glucose tolerance and a lower risk of developing diabetes.

Figure 4. Chemical structure of several RORα/γ inverse agonists and (ant)agonists

T0901317, SR1001, and 7α-hydroxycholesterol function as inverse agonists of both RORα and RORγ; cholesterol, cholesterol sulfate, and 25-hydroxycholesterol act as RORα and/or RORγ agonists; all other compounds have been reported to function as an inverse agonist or antagonist of RORγ.

Figure 5. Metabolites of the cholesterol biosynthetic pathway function as endogenous RORγ agonists

A. Shown is a schematic view of the cholesterol synthetic pathway. Zymosterol and desmosterol are among the RORγ agonists with the highest affinity. Deficiency in Fdft1 or Cyp51A1, enzymes acting upstream in the cholesterol biosynthetic pathway, inhibit the synthesis of downstream RORγ agonists subsequently leading to reduced RORγt activation and Th17 differentiation. FDT1, Farnesyl-Diphosphate Farnesyltransferase 1; SQLE, Squalene Epoxidase; LSS, Lanosterol Synthase; TM7SF2, Transmembrane 7 Superfamily Member 2 (C-14 Sterol Reductase); FAXDC2/SC4MOL, Fatty Acid Hydroxylase Domain Containing 2/Methylsterol Monooxygenase 1; NSDHL, NAD(P) Dependent Steroid Dehydrogenase-Like; HSD17B7, Hydroxysteroid (17-Beta) Dehydrogenase 7; EBP, Emopamil Binding Protein (Sterol Isomerase); SC5D, Sterol-C5-Desaturase; DHCR7, 7-Dehydrocholesterol Reductase; DHCR24, 24-Dehydrocholesterol Reductase. B. Schematic view of RORγ-mediated transcriptional activation of target genes by endogenous sterol agonists and its inhibition by antagonists. The circadian clock regulates RORγ expression and as a consequence the expression of RORγ target genes. Prox1 modulates RORγ transcriptional activity. The in vivo consensus RORE derived from ChIP-Seq analysis using liver tissue and an anti-RORγ antibody, is shown.