Transcriptional regulation of human Rev-erblpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha

Transcriptional regulation of human Rev-erblpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha. Graphical Abstract In Brief Functions for the circadian protein REV-ERB have not been extensively explored in the immune system. Amir et al. demonstrate that REV-ERB functions as a negative regulator of proinflammatory TH17 cell development and function, and REV-ERB ligands are efficacious in mouse models of autoimmunity. INTRODUCTION T helper 17 (TH17) cells are a subset of CD4+ T helper cells that preferentially secrete interleukin 17A (IL-17A), IL-17F, IL-21, and IL-22 and are important during tissue inflammation and anti-microbial and anti-fungal immunity (McGeachy and Cua, 2008). Under homeostatic conditions, TH17 cells have essential functions in protective immunity against extracellular pathogens at mucosal barriers (McGeachy and Cua, 2008). However, TH17 cells have also been associated with the pathogenesis of several autoimmune diseases, including multiple sclerosis and psoriasis (Cho, 2008; Lees et al., 2011; Nair et al., 2009), suggesting that this failure of TH17 cell homeostasis may give rise to disease. A significant amount of work has recognized key factors that drive TH17 cell development and pathogenicity. However, cell-intrinsic mechanisms that negatively regulate TH17 cell development and associated inflammatory responses have received less attention. Therefore, a more comprehensive understanding of the factors that both positively and negatively regulate TH17 cell development is necessary to better understand TH17-mediated autoimmunity and would aid in the development of novel therapeutics to treat TH17-mediated diseases. A number of studies have recognized important factors that drive TH17 cell development and pathogenicity, including both the nuclear receptors retinoic-acid-receptor-related orphan receptor and t (Ivanov et al., 2006; Yang et al., 2008). RORt is considered the lineage-defining transcription factor regulating TH17 cell development, and a considerable amount of research has elucidated genomic functions of RORt. Two other members of the nuclear receptor superfamily, REV-ERB (NR1D1) and REV-ERB (NR1D2), are often co-expressed in the same tissues as the RORs and bind the same DNA response elements, resulting in mutual cross-talk and co-regulation of their shared target genes (Kojetin and Burris, 2014). Outside of the immune system, the RORs and the REV-ERBs modulate a number of physiological processes but are best known for their functions in the regulation of the circadian rhythm, lipid, and glucose metabolic processes. The REV-ERBs are unique within the nuclear receptor superfamily in that they lack Rabbit polyclonal to USP20 the carboxy-terminal tail of their ligand-binding domain name (LBD) called the activation function 2 region (AF-2, helix 12), which is required for coactivator acknowledgement. Thus, in contrast to the RORs, which are constitutive activators of transcription, the REV-ERBs are transcriptional repressors (Kojetin and Burris, 2014). Collectively, the balance of expression of the RORs and REV-ERBs is critical for dynamic regulation of their target genes (Kojetin and Burris, 2014). While much is known about RORt-mediated regulation of TH17 cell development and function, little is known about the role of the REV-ERBs in T cell effector functions, specifically proinflammatory TH17 cell effector functions and autoimmunity. Most members of the nuclear receptor superfamily are ligand-regulated transcription factors and represent attractive therapeutic targets, including RORt. After the initial identification of several synthetic ROR modulators, including SR1001 and digoxin (Huh et al., 2011; Solt et al., 2011), countless other ROR ligands have been recognized, demonstrating the tractability of RORt-targeted treatment of TH17-mediated auto-immunity (Bronner et al., 2017). The REV-ERBs are also ligand-regulated transcription factors, and the porphyrin heme was identified as the endogenous ligand for both REV-ERB and REV-ERB (Raghuram et al., 2007; Yin et al., 2007). We as well as others have recognized and characterized Chondroitin sulfate synthetic ligands that modulate the activity of the REV-ERBs both and (Banerjee et al., 2014; Kojetin et al., 2011; Solt et al., 2012). Chondroitin sulfate We previously synthesized and characterized SR9009 and SR9011 for their activity and specificity to target the REV-ERBs, demonstrating that pharmacological modulation of REV-ERB activity affected REV-ERB-mediated processes, including regulation of the circadian rhythm, glucose, and lipid metabolic processes (Solt et al., 2012). Despite the well-documented overlap in genetic programs between the RORs and REV-ERBs in tissues outside of the immune system (Kojetin and Burris, 2014), the role for the REV-ERBs in TH17 cell development is still poorly comprehended. Furthermore, given the massive pharmaceutical effort focused on developing potent ROR-modulators, small-molecule modulators of REV-ERB activity could represent a novel therapeutic target for the treatment of TH17-mediated autoimmunity. While REV-ERB was previously demonstrated to diurnally regulate TH17 cell Chondroitin sulfate frequencies (Yu et al., 2013), its function in the context of proinflammatory settings and.