Skip to main content
SpringerLink
Log in

Retinoic Acid-Related Orphan Receptor (ROR) Inverse Agonists: Potential Therapeutic Strategies for Multiple Inflammatory Diseases?

  • Chapter
  • First Online:
Nuclear Receptors

  • 915 Accesses

Abstract

Retinoic acid-related orphan receptors (RORs) function as ligand-dependent transcription factors. Several (oxy)sterols have been identified that activate or repress ROR transcriptional activity by functioning as either ROR agonists or inverse agonists. RORs are involved in the control of many biological processes, including the regulation of differentiation and function of neural, immune, and metabolic tissues, bone, and heart. Many of the processes and functions regulated by RORs play a critical role in various pathologies, including autoimmune and other inflammatory diseases, metabolic syndrome and diabetes, neurological and psychiatric disorders, and cardiac injury. Together, these studies raised the possibility that modulation of ROR activity by synthetic ligands might be a useful approach to intervene in these diseases. This led to the identification of many synthetic ROR (inverse) agonists that repress or induce ROR transcriptional activity. Most studies have been focusing on RORγt inverse agonists that repress the generation of interleukin 17 (IL-17)-producing immune cells and the production of pro-inflammatory cytokines, such as IL-17, which play a critical role in various inflammatory diseases. Treatment of autoimmune disease in several experimental rodent models with RORγ inverse agonists was shown to reduce the production of pro-inflammatory cytokines and ameliorate the disease. Thus, ROR (inverse) agonists may potentially provide new therapeutic strategies to treat various pathologies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Acevedo N, Saaf A, Soderhall C, Melen E, Mandelin J, Pietras CO, Ezer S, Karisola P, Vendelin J, Gennas GB, Yli-Kauhaluoma J, Alenius H, von Mutius E, Doekes G, Braun-Fahrlander C, Riedler J, van Hage M, D'Amato M, Scheynius A, Pershagen G, Kere J, Pulkkinen V. Interaction between retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma. PLoS One. 2013;8:e60111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Akitsu A, Iwakura Y. Interleukin-17-producing gammadelta T (gammadelta17) cells in inflammatory diseases. Immunology. 2018;155:418–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Andre E, Conquet F, Steinmayr M, Stratton SC, Porciatti V, Becker-Andre M. Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J. 1998a;17:3867–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Andre E, Gawlas K, Becker-Andre M. A novel isoform of the orphan nuclear receptor RORbeta is specifically expressed in pineal gland and retina. Gene. 1998b;216:277–83.

    Article  CAS  PubMed  Google Scholar 

  5. Ano S, Morishima Y, Ishii Y, Yoh K, Yageta Y, Ohtsuka S, Matsuyama M, Kawaguchi M, Takahashi S, Hizawa N. Transcription factors GATA-3 and RORgammat are important for determining the phenotype of allergic airway inflammation in a murine model of asthma. J Immunol. 2013;190:1056–65.

    Article  CAS  PubMed  Google Scholar 

  6. Aquino-Martinez R, Farr JN, Weivoda MM, Negley BA, Onken JL, Thicke BS, Fulcer MM, Fraser DG, van Wijnen AJ, Khosla S, Monroe DG. miR-219a-5p regulates Rorbeta during osteoblast differentiation and in age-related bone loss. J Bone Miner Res. 2019;34:135–44.

    Article  CAS  PubMed  Google Scholar 

  7. Ardain A, Porterfield JZ, Kloverpris HN, Leslie A. Type 3 ILCs in lung disease. Front Immunol. 2019;10:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Asimus S, Palmer R, Albayaty M, Forsman H, Lundin C, Olsson M, Pehrson R, Mo J, Russell M, Carlert S, Close D, Keeling D. Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor gamma agonist AZD0284. Br J Clin Pharmacol. 2020;86:1398–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baburski AZ, Andric SA, Kostic TS. Luteinizing hormone signaling is involved in synchronization of Leydig cell's clock and is crucial for rhythm robustness of testosterone production dagger. Biol Reprod. 2019;100:1406–15.

    Article  PubMed  Google Scholar 

  10. Baglietto MG, Caridi G, Gimelli G, Mancardi M, Prato G, Ronchetto P, Cuoco C, Tassano E. RORB gene and 9q21.13 microdeletion: report on a patient with epilepsy and mild intellectual disability. Eur J Med Genet. 2014;57:44–6.

    Article  PubMed  Google Scholar 

  11. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis. 2018;77:175–87.

    Article  CAS  PubMed  Google Scholar 

  12. Banerjee D, Zhao L, Wu L, Palanichamy A, Ergun A, Peng L, Quigley C, Hamann S, Dunstan R, Cullen P, Allaire N, Guertin K, Wang T, Chao J, Loh C, Fontenot JD. Small molecule mediated inhibition of RORgamma-dependent gene expression and autoimmune disease pathology in vivo. Immunology. 2016;147:399–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barbay JK, Cummings MD, Abad M, Castro G, Kreutter KD, Kummer DA, Maharoof U, Milligan C, Nishimura R, Pierce J, Schalk-Hihi C, Spurlino J, Tanis VM, Urbanski M, Venkatesan H, Wang A, Woods C, Wolin R, Xue X, Edwards JP, Fourie AM, Leonard K. 6-Substituted quinolines as RORgammat inverse agonists. Bioorg Med Chem Lett. 2017;27:5277–83.

    Article  CAS  PubMed  Google Scholar 

  14. Bassolas-Molina H, Raymond E, Labadia M, Wahle J, Ferrer-Picon E, Panzenbeck M, Zheng J, Harcken C, Hughes R, Turner M, Smith D, Calderon-Gomez E, Esteller M, Carrasco A, Esteve M, Dotti I, Corraliza AM, Masamunt MC, Arajol C, Guardiola J, Ricart E, Nabozny G, Salas A. An RORgammat Oral inhibitor modulates IL-17 responses in peripheral blood and intestinal mucosa of Crohn’s disease patients. Front Immunol. 2018;9:2307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Beak JY, Kang HS, Huang W, Aghajanian A, Gerrish K, Jetten AM, Jensen BC. The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating mitophagy through caveolin-3. https://www.biorxiv.org/content/10.1101/2020.10.02.323410v1.

  16. Beak JY, Kang HS, Huang W, Myers PH, Bowles DE, Jetten AM, Jensen BC. The nuclear receptor RORalpha protects against angiotensin II-induced cardiac hypertrophy and heart failure. Am J Physiol Heart Circ Physiol. 2019;316:H186–200.

    Article  CAS  PubMed  Google Scholar 

  17. Bellan M, Andreoli L, Mele C, Sainaghi PP, Rigamonti C, Piantoni S, De Benedittis C, Aimaretti G, Pirisi M, Marzullo P. Pathophysiological role and therapeutic implications of vitamin D in autoimmunity: focus on chronic autoimmune diseases. Nutrients. 2020;12:789. https://doi.org/10.3390/nu12030789.

    Article  CAS  PubMed Central  Google Scholar 

  18. Borger JG, Lau M, Hibbs ML. The influence of innate lymphoid cells and unconventional T cells in chronic inflammatory lung disease. Front Immunol. 2019;10:1597. https://doi.org/10.3390/nu12030789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Boudry-Labis E, Demeer B, Le Caignec C, Isidor B, Mathieu-Dramard M, Plessis G, George AM, Taylor J, Aftimos S, Wiemer-Kruel A, Kohlhase J, Anneren G, Firth H, Simonic I, Vermeesch J, Thuresson AC, Copin H, Love DR, Andrieux J. A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features. Eur J Med Genet. 2013;56:163–70.

    Article  PubMed  Google Scholar 

  20. Bronner SM, Zbieg JR, Crawford JJ. RORgamma antagonists and inverse agonists: a patent review. Expert Opin Ther Pat. 2017;27:101–12.

    Article  CAS  PubMed  Google Scholar 

  21. Byun H, Lee HL, Liu H, Forrest D, Rudenko A, Kim IJ. Rorbeta regulates selective axon-target innervation in the mammalian midbrain. Development. 2019;146 https://doi.org/10.1242/dev.171926.

  22. Capone A, Volpe E. Transcriptional regulators of T helper 17 cell differentiation in health and autoimmune diseases. Front Immunol. 2020;11:348. https://doi.org/10.3389/fimmu.2020.00348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Carlberg C, Hooft van Huijsduijnen R, Staple JK, DeLamarter JF, Becker-Andre M. RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol Endocrinol. 1994;8:757–70.

    CAS  PubMed  Google Scholar 

  24. Castro G, Liu X, Ngo K, De Leon-Tabaldo A, Zhao S, Luna-Roman R, Yu J, Cao T, Kuhn R, Wilkinson P, Herman K, Nelen MI, Blevitt J, Xue X, Fourie A, Fung-Leung WP. RORgammat and RORalpha signature genes in human Th17 cells. PLoS One. 2017;12:e0181868.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chang MR, Lyda B, Kamenecka TM, Griffin PR. Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor gamma is therapeutic in the collagen-induced arthritis experimental model. Arthritis Rheumatol. 2014;66:579–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen Y, Wang D, Zhao Y, Huang B, Cao H, Qi D. p300 promotes differentiation of Th17 cells via positive regulation of the nuclear transcription factor RORgammat in acute respiratory distress syndrome. Immunol Lett. 2018;202:8–15.

    Article  CAS  PubMed  Google Scholar 

  27. Cherney RJ, Cornelius LAM, Srivastava A, Weigelt CA, Marcoux D, Duan JJ, Shi Q, Batt DG, Liu Q, Yip S, Wu DR, Ruzanov M, Sack J, Khan J, Wang J, Yarde M, Cvijic ME, Mathur A, Li S, Shuster D, Khandelwal P, Borowski V, Xie J, Obermeier M, Fura A, Stefanski K, Cornelius G, Tino JA, Macor JE, Salter-Cid L, Denton R, Zhao Q, Carter PH, Dhar TGM. Discovery of BMS-986251: a clinically viable, potent, and selective RORgammat inverse agonist. ACS Med Chem Lett. 2020;11:1221–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cook DN, Kang HS, Jetten AM. Retinoic Acid-Related Orphan Receptors (RORs): regulatory functions in immunity, development, circadian rhythm, and metabolism. Nucl Receptor Res. 2015;2:101185. https://doi.org/10.11131/2015/101185.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Coppola A, Cellini E, Stamberger H, Saarentaus E, Cetica V, Lal D, Djemie T, Bartnik-Glaska M, Ceulemans B, Helen Cross J, Deconinck T, Masi S, Dorn T, Guerrini R, Hoffman-Zacharska D, Kooy F, Lagae L, Lench N, Lemke JR, Lucenteforte E, Madia F, Mefford HC, Morrogh D, Nuernberg P, Palotie A, Schoonjans AS, Striano P, Szczepanik E, Tostevin A, Vermeesch JR, Van Esch H, Van Paesschen W, Waters JJ, Weckhuysen S, Zara F, De Jonghe P, Sisodiya SM, Marini C, Euro E-RESC, Epi CNVC. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia. 2019;60:689–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dai J, Choo MK, Park JM, Fisher DE. Topical ROR inverse agonists suppress inflammation in mouse models of atopic dermatitis and acute irritant dermatitis. J Invest Dermatol. 2017;137:2523–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. de Carvalho A, Bassaneze V, Forni MF, Keusseyan AA, Kowaltowski AJ, Krieger JE. Early postnatal cardiomyocyte proliferation requires high oxidative energy metabolism. Sci Rep. 2017;7:15434.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. de Wit J, Al-Mossawi MH, Huhn MH, Arancibia-Carcamo CV, Doig K, Kendrick B, Gundle R, Taylor P, McClanahan T, Murphy E, Zhang H, Barr K, Miller JR, Hu X, Aicher TD, Morgan RW, Glick GD, Zaller D, Correll C, Powrie F, Bowness P. RORgammat inhibitors suppress T(H)17 responses in inflammatory arthritis and inflammatory bowel disease. J Allergy Clin Immunol. 2016;137:960–3.

    Article  PubMed  CAS  Google Scholar 

  33. Del Barrio MG, Bourane S, Grossmann K, Schule R, Britsch S, O'Leary DD, Goulding M. A transcription factor code defines nine sensory interneuron subtypes in the mechanosensory area of the spinal cord. PLoS One. 2013;8:e77928.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Diefenbach A, Colonna M, Koyasu S. Development, differentiation, and diversity of innate lymphoid cells. Immunity. 2014;41:354–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Doebelin C, Patouret R, Garcia-Ordonez RD, Chang MR, Dharmarajan V, Novick S, Ciesla A, Campbell S, Solt LA, Griffin PR, Kamenecka TM. Identification of potent RORbeta modulators: scaffold variation. Bioorg Med Chem Lett. 2018;28:3210–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008;8:337–48.

    Article  CAS  PubMed  Google Scholar 

  37. Dzhagalov I, Giguere V, He YW. Lymphocyte development and function in the absence of retinoic acid-related orphan receptor alpha. J Immunol. 2004;173:2952–9.

    Article  CAS  PubMed  Google Scholar 

  38. Eberl G, Littman DR. The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer’s patches. Immunol Rev. 2003;195:81–90.

    Article  CAS  PubMed  Google Scholar 

  39. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORgammat in the generation of fetal lymphoid tissue inducer cells. Nat Immunol. 2004;5:64–73.

    Article  CAS  PubMed  Google Scholar 

  40. Ecoeur F, Weiss J, Kaupmann K, Hintermann S, Orain D, Guntermann C. Antagonizing retinoic acid-related-orphan receptor gamma activity blocks the T helper 17/Interleukin-17 pathway leading to attenuated pro-inflammatory human keratinocyte and skin responses. Front Immunol. 2019;10:577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ersland KM, Christoforou A, Stansberg C, Espeseth T, Mattheisen M, Mattingsdal M, Hardarson GA, Hansen T, Fernandes CP, Giddaluru S, Breuer R, Strohmaier J, Djurovic S, Nothen MM, Rietschel M, Lundervold AJ, Werge T, Cichon S, Andreassen OA, Reinvang I, Steen VM, Le Hellard S. Gene-based analysis of regionally enriched cortical genes in GWAS data sets of cognitive traits and psychiatric disorders. PLoS One. 2012;7:e31687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Farr JN, Weivoda MM, Nicks KM, Fraser DG, Negley BA, Onken JL, Thicke BS, Ruan M, Liu H, Forrest D, Hawse JR, Khosla S, Monroe DG. Osteoprotection through the deletion of the transcription factor Rorbeta in mice. J Bone Miner Res. 2018;33:720–31.

    Article  CAS  PubMed  Google Scholar 

  43. Fauber BP, Gobbi A, Robarge K, Zhou A, Barnard A, Cao J, Deng Y, Eidenschenk C, Everett C, Ganguli A, Hawkins J, Johnson AR, La H, Norman M, Salmon G, Summerhill S, Ouyang W, Tang W, Wong H. Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. Bioorg Med Chem Lett. 2015;25:2907–12.

    Article  CAS  PubMed  Google Scholar 

  44. Fauber BP, Magnuson S. Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORgamma or RORc). J Med Chem. 2014;57:5871–92.

    Article  CAS  PubMed  Google Scholar 

  45. Fitzpatrick LR, Small J, O'Connell R, Talbott G, Alton G, Zapf J. VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease. Inflammopharmacology. 2020;28:499–511.

    Article  PubMed  Google Scholar 

  46. Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11:255–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fujita-Sato S, Ito S, Isobe T, Ohyama T, Wakabayashi K, Morishita K, Ando O, Isono F. Structural basis of digoxin that antagonizes RORgamma t receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production. J Biol Chem. 2011;286:31409–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fukase Y, Sato A, Tomata Y, Ochida A, Kono M, Yonemori K, Koga K, Okui T, Yamasaki M, Fujitani Y, Nakagawa H, Koyama R, Nakayama M, Skene R, Sang BC, Hoffman I, Shirai J, Yamamoto S. Identification of novel quinazolinedione derivatives as RORgammat inverse agonist. Bioorg Med Chem. 2018;26:721–36.

    Article  CAS  PubMed  Google Scholar 

  49. Gege C. RORgammat inhibitors as potential back-ups for the phase II candidate VTP-43742 from vitae pharmaceuticals: patent evaluation of WO2016061160 and US20160122345. Expert Opin Ther Pat. 2017;27:1–8.

    Article  CAS  PubMed  Google Scholar 

  50. Gege C, Albers M, Kinzel O, Kleymann G, Schluter T, Steeneck C, Hoffmann T, Xue X, Cummings MD, Spurlino J, Milligan C, Fourie AM, Edwards JP, Leonard K, Coe K, Scott B, Pippel D, Goldberg SD. Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgammat. Bioorg Med Chem Lett. 2020;30:127205.

    Article  CAS  PubMed  Google Scholar 

  51. Gege C, Schluter T, Hoffmann T. Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORbeta and RORgammat. Bioorg Med Chem Lett. 2014;24:5265–7.

    Article  CAS  PubMed  Google Scholar 

  52. Geoffroy PA, Lajnef M, Bellivier F, Jamain S, Gard S, Kahn JP, Henry C, Leboyer M, Etain B. Genetic association study of circadian genes with seasonal pattern in bipolar disorders. Sci Rep. 2015;5:10232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Giguere V, McBroom LD, Flock G. Determinants of target gene specificity for ROR alpha 1: monomeric DNA binding by an orphan nuclear receptor. Mol Cell Biol. 1995;15:2517–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Giguere V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994;8:538–53.

    Article  CAS  PubMed  Google Scholar 

  55. Gorzin F, Amirzargar AA, Mahmoudi MJ, Rahnemoon Z, Najmi Varzaneh F, Hedayat M, Sadati S, Eskandari V, Rahmati Z, Rezaei N. FOXP3, RORgammat and IL-10 cytokine profile in chronic heart failure. Bratisl Lek Listy. 2017;118:637–41.

    CAS  PubMed  Google Scholar 

  56. Gran F, Kerstan A, Serfling E, Goebeler M, Muhammad K. Current developments in the immunology of psoriasis. Yale J Biol Med. 2020;93:97–110.

    PubMed  PubMed Central  Google Scholar 

  57. Guendisch U, Weiss J, Ecoeur F, Riker JC, Kaupmann K, Kallen J, Hintermann S, Orain D, Dawson J, Billich A, Guntermann C. Pharmacological inhibition of RORgammat suppresses the Th17 pathway and alleviates arthritis in vivo. PLoS One. 2017;12:e0188391.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Guntermann C, Piaia A, Hamel ML, Theil D, Rubic-Schneider T, Del Rio-Espinola A, Dong L, Billich A, Kaupmann K, Dawson J, Hoegenauer K, Orain D, Hintermann S, Stringer R, Patel DD, Doelemeyer A, Deurinck M, Schumann J. Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations. JCI Insight. 2017;2:e91127.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Haerian BS, Sha'ari HM, Tan HJ, Fong CY, Wong SW, Ong LC, Raymond AA, Tan CT, Mohamed Z. RORA gene rs12912233 and rs880626 polymorphisms and their interaction with SCN1A rs3812718 in the risk of epilepsy: a case-control study in Malaysia. Genomics. 2015;105:229–36.

    Article  CAS  PubMed  Google Scholar 

  60. Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity. 2012;37:463–74.

    Article  CAS  PubMed  Google Scholar 

  61. Han YH, Shin KO, Kim JY, Khadka DB, Kim HJ, Lee YM, Cho WJ, Cha JY, Lee BJ, Lee MO. A maresin 1/RORalpha/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis. J Clin Invest. 2019;129:1684–98.

    Article  PubMed  PubMed Central  Google Scholar 

  62. He B, Zhao Y, Xu L, Gao L, Su Y, Lin N, Pu J. The nuclear melatonin receptor RORalpha is a novel endogenous defender against myocardial ischemia/reperfusion injury. J Pineal Res. 2016;60:313–26.

    Article  CAS  PubMed  Google Scholar 

  63. Hintermann S, Guntermann C, Mattes H, Carcache DA, Wagner J, Vulpetti A, Billich A, Dawson J, Kaupmann K, Kallen J, Stringer R, Orain D. Synthesis and biological evaluation of New Triazolo- and Imidazolopyridine RORgammat inverse agonists. Chem Med Chem. 2016;11:2640–8.

    Article  CAS  PubMed  Google Scholar 

  64. Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM. TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol. 1994a;8:1667–80.

    CAS  PubMed  Google Scholar 

  65. Hirose T, Smith RJ, Jetten AM. ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem Biophys Res Commun. 1994b;205:1976–83.

    Article  CAS  PubMed  Google Scholar 

  66. Holgate ST. Innate and adaptive immune responses in asthma. Nat Med. 2012;18:673–83.

    Article  CAS  PubMed  Google Scholar 

  67. Holick MF. Ultraviolet B radiation: the vitamin D connection. Adv Exp Med Biol. 2017;996:137–54.

    Article  CAS  PubMed  Google Scholar 

  68. Honstein T, Werfel T. The show must go on: an update on clinical experiences and clinical studies on novel pharmaceutical developments for the treatment of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2020;20:386–94.

    Article  CAS  PubMed  Google Scholar 

  69. Hou SJ, Tsai SJ, Kuo PH, Liu YL, Yang AC, Lin E, Lan TH. An association study in the Taiwan Biobank reveals RORA as a novel locus for sleep duration in the Taiwanese population. Sleep Med. 2020;73:70–5.

    Article  PubMed  Google Scholar 

  70. Hu X, Wang Y, Hao L-Y, Liu X, Lesch CA, Sanchez BM, Wendling JM, Morgan RW, Carter LL, Toogood PL, Glick GD. Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists. Nature Chem Biol. 2015;11:141–7.

    Article  CAS  Google Scholar 

  71. Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR, Chow J, Manel N, Ciofani M, Kim SV, Cuesta A, Santori FR, Lafaille JJ, Xu HE, Gin DY, Rastinejad F, Littman DR. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature. 2011;472:486–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Igaki K, Nakamura Y, Tanaka M, Mizuno S, Yoshimatsu Y, Komoike Y, Uga K, Shibata A, Imaichi H, Takayuki S, Ishimura Y, Yamasaki M, Kanai T, Tsukimi Y, Tsuchimori N. Pharmacological effects of TAK-828F: an orally available RORgammat inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease. Inflamm Res. 2019;68:493–509.

    Article  CAS  PubMed  Google Scholar 

  73. Iizuka M, Tsuboi H, Matsuo N, Asashima H, Hirota T, Kondo Y, Iwakura Y, Takahashi S, Matsumoto I, Sumida T. A crucial role of RORgammat in the development of spontaneous Sialadenitis-like Sjogren's syndrome. J Immunol. 2015;194:56–67.

    Article  CAS  PubMed  Google Scholar 

  74. Imura C, Ueyama A, Sasaki Y, Shimizu M, Furue Y, Tai N, Tsujii K, Katayama K, Okuno T, Shichijo M, Yasui K, Yamamoto M. A novel RORgammat inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations. J Dermatol Sci. 2019;93:176–85.

    Article  CAS  PubMed  Google Scholar 

  75. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of Proinflammatory IL-17(+) T helper cells. Cell. 2006;126:1121–33.

    Article  CAS  PubMed  Google Scholar 

  76. Ivanov II, Zhou L, Littman DR. Transcriptional regulation of Th17 cell differentiation. Semin Immunol. 2007;19:409–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jabaudon D, Shnider SJ, Tischfield DJ, Galazo MJ, Macklis JD. RORbeta induces barrel-like neuronal clusters in the developing neocortex. Cereb Cortex. 2012;22:996–1006.

    Article  PubMed  Google Scholar 

  78. Jaradat M, Stapleton C, Tilley SL, Dixon D, Erikson CJ, McCaskill JG, Kang HS, Angers M, Liao G, Collins J, Grissom S, Jetten AM. Modulatory role for retinoid-related orphan receptor alpha in allergen-induced lung inflammation. Am J Respir Crit Care Med. 2006;174:1299–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Jetten AM. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal. 2009;7:e003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Jetten AM, Cook DN. (Inverse) agonists of retinoic acid-related orphan receptor gamma: regulation of immune responses, inflammation, and autoimmune disease. Annu Rev Pharmacol Toxicol. 2020;60:371–90.

    Article  CAS  PubMed  Google Scholar 

  81. Jetten AM, Takeda Y, Slominski A, Kang HS. Retinoic acid-related Orphan Receptor γ (RORγ): connecting sterol metabolism to regulation of the immune system and autoimmune disease. Curr Opion Toxicol. 2018;8:66–80.

    Article  Google Scholar 

  82. Jia L, Oh EC, Ng L, Srinivas M, Brooks M, Swaroop A, Forrest D. Retinoid-related orphan nuclear receptor RORbeta is an early-acting factor in rod photoreceptor development. Proc Natl Acad Sci U S A. 2009;106:17534–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jiang B, Duan JJ, Stachura S, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Weigelt CA, Khan J, Sack JS, Wu DR, Yarde M, Shen DR, Galella MA, Mathur A, Zhao Q, Salter-Cid LM, Carter PH, Dhar TGM. Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2- yl)phenyl)pyrrolidines as novel RORgammat inverse agonists. Bioorg Med Chem Lett. 2020;30:127392.

    Article  CAS  PubMed  Google Scholar 

  84. Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y. Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol Endocrinol. 2010;24:923–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kabata H, Moro K, Koyasu S, Asano K. Group 2 innate lymphoid cells and asthma. Allergol Int. 2015;64:227–34.

    Article  CAS  PubMed  Google Scholar 

  86. Kallen J, Izaac A, Be C, Arista L, Orain D, Kaupmann K, Guntermann C, Hoegenauer K, Hintermann S. Structural states of RORgammat: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds. ChemMedChem. 2017;12:1014–21.

    Article  CAS  PubMed  Google Scholar 

  87. Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B. Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2 A. J Biol Chem. 2004;279:14033–8.

    Article  CAS  PubMed  Google Scholar 

  88. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure. 2002;10:1697–707.

    Article  CAS  PubMed  Google Scholar 

  89. Kang EG, Wu S, Gupta A, von Mackensen YL, Siemetzki H, Freudenberg JM, Wigger-Alberti W, Yamaguchi Y. A phase I randomized controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test. Br J Dermatol. 2018;178:1427–9.

    Article  CAS  PubMed  Google Scholar 

  90. Koch SC, Del Barrio MG, Dalet A, Gatto G, Gunther T, Zhang J, Seidler B, Saur D, Schule R, Goulding M. RORbeta spinal interneurons gate sensory transmission during locomotion to secure a fluid walking gait. Neuron. 2017;96(1419–1431):e1415.

    Google Scholar 

  91. Kojetin DJ, Burris TP. REV-ERB and ROR nuclear receptors as drug targets. Nature Rev Drug Discov. 2014;13:197–216.

    Article  CAS  Google Scholar 

  92. Koncsos G, Varga ZV, Baranyai T, Boengler K, Rohrbach S, Li L, Schluter KD, Schreckenberg R, Radovits T, Olah A, Matyas C, Lux A, Al-Khrasani M, Komlodi T, Bukosza N, Mathe D, Deres L, Bartekova M, Rajtik T, Adameova A, Szigeti K, Hamar P, Helyes Z, Tretter L, Pacher P, Merkely B, Giricz Z, Schulz R, Ferdinandy P. Diastolic dysfunction in prediabetic male rats: role of mitochondrial oxidative stress. Am J Physiol Heart Circ Physiol. 2016;311:H927–43.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kopmels B, Mariani J, Delhaye-Bouchaud N, Audibert F, Fradelizi D, Wollman EE. Evidence for a hyperexcitability state of staggerer mutant mice macrophages. J Neurochem. 1992;58:192–9.

    Article  CAS  PubMed  Google Scholar 

  94. Kummer DA, Cummings MD, Abad M, Barbay J, Castro G, Wolin R, Kreutter KD, Maharoof U, Milligan C, Nishimura R, Pierce J, Schalk-Hihi C, Spurlino J, Urbanski M, Venkatesan H, Wang A, Woods C, Xue X, Edwards JP, Fourie AM, Leonard K. Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORgammat. Bioorg Med Chem Lett. 2017;27:2047–57.

    Article  CAS  PubMed  Google Scholar 

  95. Kurebayashi S, Nakajima T, Kim SC, Chang CY, McDonnell DP, Renaud JP, Jetten AM. Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma. Biochem Biophys Res Commun. 2004;315:919–27.

    Article  CAS  PubMed  Google Scholar 

  96. Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, Jetten AM. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A. 2000;97:10132–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lai YC, Kao CF, Lu ML, Chen HC, Chen PY, Chen CH, Shen WW, Wu JY, Lu RB, Kuo PH. Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder. PLoS One. 2015;10:e0121245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Lal D, Ruppert AK, Trucks H, Schulz H, de Kovel CG, Kasteleijn-Nolst Trenite D, Sonsma AC, Koeleman BP, Lindhout D, Weber YG, Lerche H, Kapser C, Schankin CJ, Kunz WS, Surges R, Elger CE, Gaus V, Schmitz B, Helbig I, Muhle H, Stephani U, Klein KM, Rosenow F, Neubauer BA, Reinthaler EM, Zimprich F, Feucht M, Moller RS, Hjalgrim H, De Jonghe P, Suls A, Lieb W, Franke A, Strauch K, Gieger C, Schurmann C, Schminke U, Nurnberg P, Consortium E, Sander T. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLoS Genet. 2015;11:e1005226.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, Pouly S, Murphy AJ, Valenzuela DM, Yancopoulos GD, Becher B, Littman DR, Neurath MF. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology. 2009;136:257–67.

    Article  CAS  PubMed  Google Scholar 

  100. LeVan TD, Xiao P, Kumar G, Kupzyk K, Qiu F, Klinkebiel D, Eudy J, Cowan K, Berger AM. Genetic variants in circadian rhythm genes and self-reported sleep quality in women with breast cancer. J Circadian Rhythms. 2019;17:6. https://doi.org/10.5334/jcr.184.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Li B, Huang L, Lv P, Li X, Liu G, Chen Y, Wang Z, Qian X, Shen Y, Li Y, Fang W. The role of Th17 cells in psoriasis. Immunol Res. 2020;68:296–309.

    Article  CAS  PubMed  Google Scholar 

  102. Li X, Anderson M, Collin D, Muegge I, Wan J, Brennan D, Kugler S, Terenzio D, Kennedy C, Lin S, Labadia ME, Cook B, Hughes R, Farrow NA. Structural studies unravel the active conformation of apo RORgammat nuclear receptor and a common inverse agonism of two diverse classes of RORgammat inhibitors. J Biol Chem. 2017;292:11618–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liljevald M, Rehnberg M, Soderberg M, Ramnegard M, Borjesson J, Luciani D, Krutrok N, Branden L, Johansson C, Xu X, Bjursell M, Sjogren AK, Hornberg J, Andersson U, Keeling D, Jirholt J. Retinoid-related orphan receptor gamma (RORgamma) adult induced knockout mice develop lymphoblastic lymphoma. Autoimmun Rev. 2016;15:1062–70.

    Article  CAS  PubMed  Google Scholar 

  104. Lima LC, Queiroz GA, Costa RDS, Alcantara-Neves NM, Marques CR, Costa GNO, Barreto ML, Figueiredo CAV, Carneiro VL. Genetic variants in RORA are associated with asthma and allergy markers in an admixed population. Cytokine. 2019;113:177–84.

    Article  CAS  PubMed  Google Scholar 

  105. Liu H, Aramaki M, Fu Y, Forrest D. Retinoid-related orphan receptor beta and transcriptional control of neuronal differentiation. Curr Top Dev Biol. 2017;125:227–55.

    Article  CAS  PubMed  Google Scholar 

  106. Liu H, Kim SY, Fu Y, Wu X, Ng L, Swaroop A, Forrest D. An isoform of retinoid-related orphan receptor beta directs differentiation of retinal amacrine and horizontal interneurons. Nat Commun. 2013;4:1813. https://doi.org/10.1038/ncomms2793.

    Article  CAS  PubMed  Google Scholar 

  107. Lo BC, Canals Hernaez D, Scott RW, Hughes MR, Shin SB, Underhill TM, Takei F, McNagny KM. The transcription factor RORalpha preserves ILC3 lineage identity and function during chronic intestinal infection. J Immunol. 2019;203:3209–15.

    Article  CAS  PubMed  Google Scholar 

  108. Lo BC, Gold MJ, Hughes MR, Antignano F, Valdez Y, Zaph C, Harder KW, McNagny KM. The orphan nuclear receptor RORalpha and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease. Sci Immunol. 2016;1:eaaf8864. https://doi.org/10.1126/sciimmunol.aaf8864.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Luckel C, Picard FSR, Huber M. Tc17 biology and function: novel concepts. Eur J Immunol. 2020; https://doi.org/10.1002/eji.202048627.

  110. McGinley AM, Edwards SC, Raverdeau M, Mills KHG. Th17cells, gammadelta T cells and their interplay in EAE and multiple sclerosis. J Autoimmun. 2018;S0896-8411(18)30007-6 https://doi.org/10.1016/j.jaut.2018.01.001.

  111. Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, Deodhar A, Newmark R, Feng J, Erondu N, Nirula A. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370:2295–306.

    Article  PubMed  CAS  Google Scholar 

  112. Medvedev A, Chistokhina A, Hirose T, Jetten AM. Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene. Genomics. 1997;46:93–102.

    Article  CAS  PubMed  Google Scholar 

  113. Medvedev A, Yan ZH, Hirose T, Giguere V, Jetten AM. Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene. 1996;181:199–206.

    Article  CAS  PubMed  Google Scholar 

  114. Montaldo E, Juelke K, Romagnani C. Group 3 innate lymphoid cells (ILC3s): origin, differentiation, and plasticity in humans and mice. Eur J Immunol. 2015;45:2171–82.

    Article  CAS  PubMed  Google Scholar 

  115. Nakagawa Y, O’Leary DD. Dynamic patterned expression of orphan nuclear receptor genes RORalpha and RORbeta in developing mouse forebrain. Dev Neurosci. 2003;25:234–44.

    Article  CAS  PubMed  Google Scholar 

  116. Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007;356:1140–51.

    Article  PubMed  Google Scholar 

  117. Oishi K, Aramaki M, Nakajima K. Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4. Proc Natl Acad Sci U S A. 2016;113:3371–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ono Y, Tsuboi H, Moriyama M, Asashima H, Kudo H, Takahashi H, Honda F, Abe S, Kondo Y, Takahashi S, Matsumoto I, Nakamura S, Sumida T. RORgammat antagonist improves Sjogren’s syndrome-like sialadenitis through downregulation of CD25. Oral Dis. 2020;26:766–77.

    Article  PubMed  Google Scholar 

  119. Ouvry G, Bouix-Peter C, Ciesielski F, Chantalat L, Christin O, Comino C, Duvert D, Feret C, Harris CS, Lamy L, Luzy AP, Musicki B, Orfila D, Pascau J, Parnet V, Perrin A, Pierre R, Polge G, Raffin C, Rival Y, Taquet N, Thoreau E, Hennequin LF. Discovery of phenoxyindazoles and phenylthioindazoles as RORgamma inverse agonists. Bioorg Med Chem Lett. 2016;26:5802–8.

    Article  CAS  PubMed  Google Scholar 

  120. Palmer MT, Lee YK, Maynard CL, Oliver JR, Bikle DD, Jetten AM, Weaver CT. Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells. J Biol Chem. 2011;286:997–1004.

    Article  CAS  PubMed  Google Scholar 

  121. Patouret R, Doebelin C, Garcia-Ordonez RD, Chang MR, Ruiz C, Cameron MD, Griffin PR, Kamenecka TM. Identification of an aminothiazole series of RORbeta modulators. Bioorg Med Chem Lett. 2018;28:1178–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Philips RL, Chen MW, McWilliams DC, Belmonte PJ, Constans MM, Shapiro VS. HDAC3 is required for the downregulation of RORgammat during Thymocyte positive selection. J Immunol. 2016;197:541–54.

    Article  CAS  PubMed  Google Scholar 

  123. Philips RL, McCue SA, Rajcula MJ, Shapiro VS. Cutting edge: HDAC3 protects double-positive Thymocytes from P2X7 receptor-induced cell death. J Immunol. 2019;202:1033–8.

    Article  CAS  PubMed  Google Scholar 

  124. Qiu Z, Wei Y, Song Q, Du B, Wang H, Chu Y, Hu Y. The role of myocardial mitochondrial quality control in heart failure. Front Pharmacol. 2019;10:1404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rene O, Fauber BP, Boenig Gde L, Burton B, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, Kiefer JR, Liimatta M, Lockey P, Norman M, Ouyang W, Wallweber HA, Wong H. Minor structural change to tertiary sulfonamide RORc ligands led to opposite mechanisms of action. ACS Med Chem Lett. 2015;6:276–81.

    Article  CAS  PubMed  Google Scholar 

  126. Roforth MM, Khosla S, Monroe DG. Identification of Rorbeta targets in cultured osteoblasts and in human bone. Biochem Biophys Res Comm. 2013;440:768–73.

    Article  CAS  PubMed  Google Scholar 

  127. Roforth MM, Liu G, Khosla S, Monroe DG. Examination of nuclear receptor expression in osteoblasts reveals Rorbeta as an important regulator of osteogenesis. J Bone Miner Res. 2012;27:891–901.

    Article  CAS  PubMed  Google Scholar 

  128. Rossini L, Moroni RF, Tassi L, Watakabe A, Yamamori T, Spreafico R, Garbelli R. Altered layer-specific gene expression in cortical samples from patients with temporal lobe epilepsy. Epilepsia. 2011;52:1928–37.

    Article  CAS  PubMed  Google Scholar 

  129. Rudolf G, Lesca G, Mehrjouy MM, Labalme A, Salmi M, Bache I, Bruneau N, Pendziwiat M, Fluss J, de Bellescize J, Scholly J, Moller RS, Craiu D, Tommerup N, Valenti-Hirsch MP, Schluth-Bolard C, Sloan-Bena F, Helbig KL, Weckhuysen S, Edery P, Coulbaut S, Abbas M, Scheffer IE, Tang S, Myers CT, Stamberger H, Carvill GL, Shinde DN, Mefford HC, Neagu E, Huether R, Lu HM, Dica A, Cohen JS, Iliescu C, Pomeran C, Rubenstein J, Helbig I, Sanlaville D, Hirsch E, Szepetowski P. Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur J Hum Genet. 2016;24:1761–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR. Identification of natural RORgamma ligands that regulate the development of lymphoid cells. Cell Metab. 2015;21:286–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Schaeren-Wiemers N, Andre E, Kapfhammer JP, Becker-Andre M. The expression pattern of the orphan nuclear receptor RORbeta in the developing and adult rat nervous system suggests a role in the processing of sensory information and in circadian rhythm. Eur J Neurosci. 1997;9:2687–701.

    Article  CAS  PubMed  Google Scholar 

  132. Scheepstra M, Leysen S, van Almen GC, Miller JR, Piesvaux J, Kutilek V, van Eenennaam H, Zhang H, Barr K, Nagpal S, Soisson SM, Kornienko M, Wiley K, Elsen N, Sharma S, Correll CC, Trotter BW, van der Stelt M, Oubrie A, Ottmann C, Parthasarathy G, Brunsveld L. Identification of an allosteric binding site for RORgammat inhibition. Nat Commun. 2015;6:8833.

    Article  PubMed  CAS  Google Scholar 

  133. Scoville SD, Mundy-Bosse BL, Zhang MH, Chen L, Zhang X, Keller KA, Hughes T, Chen L, Cheng S, Bergin SM, Mao HC, McClory S, Yu J, Carson WE 3rd, Caligiuri MA, Freud AG. A progenitor cell expressing transcription factor RORgammat generates all human innate lymphoid cell subsets. Immunity. 2016;44:1140–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Shirai J, Tomata Y, Kono M, Ochida A, Fukase Y, Sato A, Masada S, Kawamoto T, Yonemori K, Koyama R, Nakagawa H, Nakayama M, Uga K, Shibata A, Koga K, Okui T, Shirasaki M, Skene R, Sang B, Hoffman I, Lane W, Fujitani Y, Yamasaki M, Yamamoto S. Discovery of orally efficacious RORgammat inverse agonists, part 1: identification of novel phenylglycinamides as lead scaffolds. Bioorg Med Chem. 2018;26:483–500.

    Article  CAS  PubMed  Google Scholar 

  135. Slominski AT, Brozyna AA, Skobowiat C, Zmijewski MA, Kim TK, Janjetovic Z, Oak AS, Jozwicki W, Jetten AM, Mason RS, Elmets C, Li W, Hoffman RM, Tuckey RC. On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol. 2018;177:159–70.

    Article  CAS  PubMed  Google Scholar 

  136. Slominski AT, Brozyna AA, Zmijewski MA, Janjetovic Z, Kim TK, Slominski RM, Tuckey RC, Mason RS, Jetten AM, Guroji P, Reichrath J, Elmets C, Athar M. The role of classical and novel forms of vitamin D in the pathogenesis and progression of nonmelanoma skin cancers. Adv Exp Med Biol. 2020a;1268:257–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Slominski AT, Chaiprasongsuk A, Janjetovic Z, Kim TK, Stefan J, Slominski RM, Hanumanthu VS, Raman C, Qayyum S, Song Y, Song Y, Panich U, Crossman DK, Athar M, Holick MF, Jetten AM, Zmijewski MA, Zmijewski J, Tuckey RC. Photoprotective properties of vitamin D and Lumisterol Hydroxyderivatives. Cell Biochem Biophys. 2020b;78:165–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Slominski AT, Kim TK, Hobrath JV, Janjetovic Z, Oak ASW, Postlethwaite A, Lin Z, Li W, Takeda Y, Jetten AM, Tuckey RC. Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. Sci Rep. 2017a;7:11434.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, Li W, Tuckey RC, Jetten AM. Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORalpha and RORgamma. J Steroid Biochem Mol Biol. 2017b;173:42–56.

    Article  CAS  PubMed  Google Scholar 

  140. Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EKY, Tuckey RC. Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. Sci Rep. 2015;5:14875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, Wang J, Postlethwaite A, Li W, Tuckey RC, Jetten AM. RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J. 2014;28:2775–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Slominski RM, Stefan J, Athar M, Holick MF, Jetten AM, Raman C, Slominski AT. COVID-19 and vitamin D: a lesson from the skin. Exp Dermatol. 2020c; https://doi.org/10.1111/exd.14170.

  143. Smith SH, Peredo CE, Takeda Y, Bui T, Neil J, Rickard D, Millerman E, Therrien JP, Nicodeme E, Brusq JM, Birault V, Viviani F, Hofland H, Jetten AM, Cote-Sierra J. Development of a topical treatment for psoriasis targeting RORgamma: from bench to skin. PLoS One. 2016;11:e0147979.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Solt LA, Burris TP. Action of RORs and their ligands in (patho)physiology. Trends Endocrinol Metab. 2012;23:619–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidovic D, Schurer SC, Xu J, Wagoner G, Drew PD, Griffin PR, Burris TP. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011;472:491–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Soroosh P, Wu J, Xue X, Song J, Sutton SW, Sablad M, Yu J, Nelen MI, Liu X, Castro G, Luna R, Crawford S, Banie H, Dandridge RA, Deng X, Bittner A, Kuei C, Tootoonchi M, Rozenkrants N, Herman K, Gao J, Yang XV, Sachen K, Ngo K, Fung-Leung WP, Nguyen S, de Leon-Tabaldo A, Blevitt J, Zhang Y, Cummings MD, Rao T, Mani NS, Liu C, McKinnon M, Milla ME, Fourie AM, Sun S. Oxysterols are agonist ligands of RORgammat and drive Th17 cell differentiation. Proc Natl Acad Sci U S A. 2014;111:12163–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Stapleton CM, Jaradat M, Dixon D, Kang HS, Kim SC, Liao G, Carey MA, Cristiano J, Moorman MP, Jetten AM. Enhanced susceptibility of staggerer (RORalphasg/sg) mice to lipopolysaccharide-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol. 2005;289:L144–52.

    Article  CAS  PubMed  Google Scholar 

  148. Steeneck C, Gege C, Kinzel O, Albers M, Kleymann G, Schluter T, Schulz A, Xue X, Cummings MD, Fourie AM, Leonard KA, Scott B, Edwards JP, Hoffmann T, Goldberg SD. Discovery and optimization of new oxadiazole substituted thiazole RORgammat inverse agonists through a bioisosteric amide replacement approach. Bioorg Med Chem Lett. 2020;30:127174.

    Article  CAS  PubMed  Google Scholar 

  149. Stehlin C, Wurtz JM, Steinmetz A, Greiner E, Schule R, Moras D, Renaud JP. X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation. EMBO J. 2001;20:5822–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schule R. All-trans retinoic acid is a ligand for the orphan nuclear receptor RORbeta. Nat Struct Biol. 2003;10:820–5.

    Article  CAS  PubMed  Google Scholar 

  151. Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014;370:1209–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sun M, He C, Chen L, Yang W, Wu W, Chen F, Cao AT, Yao S, Dann SM, Dhar TGM, Salter-Cid L, Zhao Q, Liu Z, Cong Y. RORgammat represses IL-10 production in Th17 cells to maintain their pathogenicity in inducing intestinal inflammation. J Immunol. 2019a;202:79–92.

    Article  CAS  PubMed  Google Scholar 

  153. Sun N, Guo H, Wang Y. Retinoic acid receptor-related orphan receptor gamma-t (RORgammat) inhibitors in clinical development for the treatment of autoimmune diseases: a patent review (2016-present). Expert Opin Ther Pat. 2019b;29:663–74.

    Article  PubMed  CAS  Google Scholar 

  154. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science. 2000;288:2369–73.

    Article  CAS  PubMed  Google Scholar 

  155. Suzuki S, Nakamura T, Saito R, Terauchi Y, Kawai K, Takimoto-Kamimura M, Kurita N. Structural change of retinoic-acid receptor-related orphan receptor induced by binding of inverse-agonist: molecular dynamics and ab initio molecular orbital simulations. Comput Struct Biotechnol J. 2020;18:1676–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Takaishi M, Ishizaki M, Suzuki K, Isobe T, Shimozato T, Sano S. Oral administration of a novel RORgammat antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17. J Dermatol Sci. 2017;85:12–9.

    Article  CAS  PubMed  Google Scholar 

  157. Tilley SL, Jaradat M, Stapleton C, Dixon D, Hua X, Erikson CJ, McCaskill JG, Chason KD, Liao G, Jania L, Koller BH, Jetten AM. Retinoid-related orphan receptor gamma controls immunoglobulin production and Th1/Th2 cytokine balance in the adaptive immune response to allergen. J Immunol. 2007;178:3208–18.

    Article  CAS  PubMed  Google Scholar 

  158. Tuckey RC, Cheng CYS, Slominski AT. The serum vitamin D metabolome: what we know and what is still to discover. J Steroid Biochem Mol Biol. 2019;186:4–21.

    Article  CAS  PubMed  Google Scholar 

  159. Tug E, Ergun MA, Percin EF. Clinical findings in cases with 9q deletion encompassing the 9q21.11q21.32 region. Turk J Pediatr. 2018;60:94–8.

    Article  PubMed  Google Scholar 

  160. Ueda E, Kurebayashi S, Sakaue M, Backlund M, Koller B, Jetten AM. High incidence of T-cell lymphomas in mice deficient in the retinoid- related orphan receptor RORgamma. Cancer Res. 2002;62:901–9.

    CAS  PubMed  Google Scholar 

  161. Varshney P, Narasimhan A, Mittal S, Malik G, Sardana K, Saini N. Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis. Sci Rep. 2016;6:19295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Wacker M, Holick MF. Sunlight and vitamin D: a global perspective for health. Dermatoendocrinol. 2013;5:51–108.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Wang Y, Cai W, Cheng Y, Yang T, Liu Q, Zhang G, Meng Q, Han F, Huang Y, Zhou L, Xiang Z, Zhao YG, Xu Y, Cheng Z, Lu S, Wu Q, Xiang JN, Elliott JD, Leung S, Ren F, Lin X. Discovery of Biaryl amides as potent, orally bioavailable, and CNS penetrant RORgammat inhibitors. ACS Med Chem Lett. 2015;6:787–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Wang Y, Cai W, Tang T, Liu Q, Yang T, Yang L, Ma Y, Zhang G, Huang Y, Song X, Orband-Miller LA, Wu Q, Zhou L, Xiang Z, Xiang JN, Leung S, Shao L, Lin X, Lobera M, Ren F. From RORgammat agonist to two types of RORgammat inverse agonists. ACS Med Chem Lett. 2018;9:120–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Wang Y, Cai W, Zhang G, Yang T, Liu Q, Cheng Y, Zhou L, Ma Y, Cheng Z, Lu S, Zhao YG, Zhang W, Xiang Z, Wang S, Yang L, Wu Q, Orband-Miller LA, Xu Y, Zhang J, Gao R, Huxdorf M, Xiang JN, Zhong Z, Elliott JD, Leung S, Lin X. Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORgammat inhibitors. Bioorg Med Chem. 2014;22:692–702.

    Article  PubMed  CAS  Google Scholar 

  166. Wei Z, Wang Y, Zhang K, Liao Y, Ye P, Wu J, Wang Y, Li F, Yao Y, Zhou Y, Liu J. Inhibiting the Th17/IL-17A-related inflammatory responses with digoxin confers protection against experimental abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2014;34:2429–38.

    Article  CAS  PubMed  Google Scholar 

  167. Weng X, Liu Y, Cui S, Cheng B. The role of RORalpha in salivary gland lesions in patients with primary Sjogren’s syndrome. Arthritis Res Ther. 2018;20:205. https://doi.org/10.1186/s13075-018-1698-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Whitehead GS, Kang HS, Thomas SY, Medvedev A, Karcz TP, Izumi G, Nakano K, Makarov SS, Nakano H, Jetten AM, Cook DN. Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by a RORgammat inverse agonist. JCI Insight. 2019;5:e125528. https://doi.org/10.1172/jci.insight.125528.

    Article  Google Scholar 

  169. Wiltschko AB, Johnson MJ, Iurilli G, Peterson RE, Katon JM, Pashkovski SL, Abraira VE, Adams RP, Datta SR. Mapping sub-second structure in mouse behavior. Neuron. 2015;88:1121–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Withers DR, Hepworth MR, Wang X, Mackley EC, Halford EE, Dutton EE, Marriott CL, Brucklacher-Waldert V, Veldhoen M, Kelsen J, Baldassano RN, Sonnenberg GF. Transient inhibition of ROR-gammat therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat Med. 2016;22:319–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E, Camelo A, Barlow JL, Neill DR, Panova V, Koch U, Radtke F, Hardman CS, Hwang YY, Fallon PG, McKenzie AN. Transcription factor RORalpha is critical for nuocyte development. Nat Immunol. 2012;13:229–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Xiao L, Zhang Z, Luo X, Yang H, Li F, Wang N. Retinoid acid receptor-related orphan receptor alpha (RORalpha) regulates macrophage M2 polarization via activation of AMPKalpha. Mol Immunol. 2016;80:17–23.

    Article  CAS  PubMed  Google Scholar 

  173. Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C, Wu C, Baloglu E, Schmidt D, Ramesh R, Lobera M, Sundrud MS, Tsai PY, Xiang Z, Wang J, Xu Y, Lin X, Kretschmer K, Rahl PB, Young RA, Zhong Z, Hafler DA, Regev A, Ghosh S, Marson A, Kuchroo VK. Small-molecule RORgammat antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity. 2014;40:477–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Xu L, Su Y, Zhao Y, Sheng X, Tong R, Ying X, Gao L, Ji Q, Gao Y, Yan Y, Yuan A, Wu F, Lan F, Pu J. Melatonin differentially regulates pathological and physiological cardiac hypertrophy: crucial role of circadian nuclear receptor RORalpha signaling. J Pineal Res. 2019;67:e12579.

    Article  PubMed  Google Scholar 

  175. Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J Biol Chem. 2011;286:22707–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Xue X, Soroosh P, De Leon-Tabaldo A, Luna-Roman R, Sablad M, Rozenkrants N, Yu J, Castro G, Banie H, Fung-Leung WP, Santamaria-Babi L, Schlueter T, Albers M, Leonard K, Budelsky AL, Fourie AM. Pharmacologic modulation of RORgammat translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. Sci Rep. 2016;6:37977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yamamoto E, Jorgensen TN. Immunological effects of vitamin D and their relations to autoimmunity. J Autoimmun. 2019;100:7–16.

    Article  CAS  PubMed  Google Scholar 

  178. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28:29–39.

    Article  CAS  PubMed  Google Scholar 

  179. Yuan Y, Hou X, Zhang J, Chen Y, Feng Y, Su Z. Genetic variations in RORalpha are associated with chronic obstructive pulmonary disease. J Hum Genet. 2014;59:430–6.

    Article  CAS  PubMed  Google Scholar 

  180. Zang M, Zhao Y, Gao L, Zhong F, Qin Z, Tong R, Ai L, Petersen L, Yan Y, Gao Y, Zhu C, Pu J. The circadian nuclear receptor RORalpha negatively regulates cerebral ischemia-reperfusion injury and mediates the neuroprotective effects of melatonin. Biochim Biophys Acta Mol basis Dis. 2020;1866:165890. https://doi.org/10.1016/j.bbadis.2020.165890.

    Article  CAS  PubMed  Google Scholar 

  181. Zhao Y, Xu L, Ding S, Lin N, Ji Q, Gao L, Su Y, He B, Pu J. Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-alpha in diabetic cardiomyopathy. J Pineal Res. 2017;62 https://doi.org/10.1111/jpi.12378.

  182. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128:3716–26.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

Research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institutes of Health: NIH Z01-ES-101585 (AMJ), 1R01AR073004-01A1, R01AR071189-01A1, and R21 AI152047-01A1, and VA merit 1I01BX004293-01A1 (ATS), NIH (R01HL140067); Hugh A. McAllister Research Foundation (BCJ).

Author information

Authors and Affiliations

  1. Cell Biology Section, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA

    Anton M. Jetten

  2. McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Ju Youn Beak & Brian Jensen

  3. Department of Dermatology, Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL, USA

    Andrzej T. Slominski

Authors
  1. Anton M. Jetten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ju Youn Beak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrzej T. Slominski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anton M. Jetten .

Editor information

Editors and Affiliations

  1. School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

    Mostafa Z. Badr

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Jetten, A.M., Beak, J.Y., Slominski, A.T., Jensen, B. (2021). Retinoic Acid-Related Orphan Receptor (ROR) Inverse Agonists: Potential Therapeutic Strategies for Multiple Inflammatory Diseases?. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_14

Download citation

Publish with us

Policies and ethics

Search

Navigation