MECHANISMS OF RORΑ-DEPENDENT EFFECTS OF MELATONIN
- Authors: Kuklina E.M.1
-
Affiliations:
- Perm Federal Research Center, Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences
- Section: Joint Immunology Forum 2024
- URL: https://rusimmun.ru/jour/article/view/16625
- DOI: https://doi.org/10.46235/1028-7221-16625-MOR
- ID: 16625
Cite item
Full Text
Abstract
Abstract
The transcription factor RORα has not traditionally been attributed a fundamental role in the development of Th17 cells, but recent studies have shown that it is necessary for the formation of a pathogenic variant of Th17 cells, the so-called Th1-polarized Th17 (Th17.1). Since the transcriptional activity of RORα depends on ligand binding, the search for such ligands is highly relevant, and in this regard, melatonin is of particular interest - the question of the ability of RORα to directly bind melatonin remains open today; data on this problem are extremely contradictory. In 1995, I. Wiesenberg and colleagues identified RORα as a nuclear receptor for melatonin, demonstrating the hormone's ability to enhance the binding of this factor to DNA and determining the dissociation constant for the interaction of RORα with melatonin using classical Scatchard analysis. In 2011, P.J. Lardone and colleagues "rediscovered" RORα as a receptor for melatonin by demonstrating the coprecipitation of melatonin with RORα. And in 2016 A.J. Slominski and colleagues published a paper that cast doubt on the possibility of melatonin binding to RORα based on molecular modeling of ligand-receptor interactions supported by functional studies. However, a careful analysis of these data indicates the ambiguity of this conclusion, allowing us to speak, rather, of medium or low binding affinity of the hormone to RORα, but not of its absence. This conclusion is also supported by the fact that RORα mediates many of the effects of melatonin, both physiological and pharmacological, including the regulation of circadian rhythms and oxidative metabolism, neuro- and cardioprotection, and control of the immune response. In general, the data available today allow us to consider the transcription factor RORα as a receptor for melatonin with medium affinity, although indirect regulation of this factor by the hormone is not excluded, and RORα-dependent mechanisms should contribute to the cell response to melatonin both under physiological conditions and and in the case of pharmacological use of the hormone.
About the authors
Elena M. Kuklina
Perm Federal Research Center, Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences
Author for correspondence.
Email: ibis_07@mail.ru
Dr. Sc, (Biol.), Leading Research Officer at the Laboratory of Immunoregulation, Perm Federal Research Center, Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences
Russian FederationReferences
- 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 M.I., Blevitt J., Xue X., Fourie A., Fung-Leung W.P. RORγt and RORα signature genes in human Th17 cells. PLoS One, 2017, Vol. 12, no. 8, e0181868. doi: 10.1371/journal.pone.0181868
- Ermisch M., Firla B., Steinhilber D. Protein kinase A activates and phosphorylates RORα4 in vitro and takes part in RORα activation by CaMK-IV. Biochem. Biophys. Res.Commun., 2011, Vol. 408, no. 3, pp. 442–446. doi: 10.1016/j.bbrc.2011.04.046
- Fang N., Chunyi H., Wenqi S., Ying X., Yeqi G., Le W., Qing P., Russel J. R., Lifeng L. Identification of a novel melatonin-binding nuclear receptor: Vitamin D receptor. J. Pineal Res., 2018, Vol. 68, no.1, e12618. doi: org/10.1111/jpi.12618
- Fang Y., Zhang J., Li Y., Guo X., Li J., Zhong R., Zhang X. Melatonin-induced demethylation of antioxidant genes increases antioxidant capacity through RORalpha in cumulus cells of prepubertal lambs. Free Radical Biol. Med., 2019, Vol. 131, pp. 173–183. doi: 10.1016/j.freeradbiomed.2018.11.027
- García J.A., Volt H., Venegas C., Doerrier C., Escames G., López L.C., Acuña-Castroviejo D. Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J., 2015, Vol. 29, pp. 3863–3875. doi: 10.1096/fj.15-273656
- Glebezdina N.S., Nekrasova I.V., Olina A.A., Sadykova G.K., Kuklina E.M. Differentiation of T cells producing interleukin‐17 (Th17) against the background of exogenous melatonin during pregnancy. J. Pineal. Res., 2023, e12904. doi: 10.1111/jpi.12904
- Hall J.A., Pokrovskii M., Kroehling L., Kim B.R., Kim S.Y., Wu L., Lee J.Y., Littman D.R. Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity, 2022, Vol. 55, no. 11, pp. 2027-2043. doi: 10.1016/j.immuni.2022.09.013
- He B., Zhao Y., Xu L., Gao L., Su Y., Lin N., Pu J. The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury. J. Pineal Res., 2016, Vol. 60, pp. 313–326. doi: 10.1111/jpi.12312
- Huang H., Liu X., Chen D., Lu Y., Li J., Du F., Zhang C., Lu L. Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α. Int. Immunopharmacol., 2020, Vol. 83, 106365. doi: 10.1016/j.intimp.2020.106365
- Hwang E.J., Lee J.M., Jeong J., Park J.H., Yang Y., Lim J.S., Kim J.H., Baek S.H., Kim K.I. SUMOylation of RORα potentiates transcriptional activation function. Biochem. Biophys. Res. Commun., 2009, Vol. 378, pp. 513–517. doi: 10.1016/j.bbrc.2008.11.072
- Kang J., Chen H., Zhang F., Yan T., Fan W., Jiang L., He H., Huang F. RORα Regulates Odontoblastic Differentiation and Mediates the Pro-Odontogenic Effect of Melatonin on Dental Papilla Cells. Molecules, 2021, Vol. 26, 1098. doi: 10.1111/jpi.12378. doi: 10.3390/molecules26041098
- Kato K., Hirai K., Nishiyama K., Uchikawa O., Fukatsu K., Ohkawa S., Kawamata Y., Hinuma S., Miyamoto M. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology, 2005, Vol. 48, no. 2, pp. 301–310. doi: 10.1016/j.neuropharm.2004.09.007
- Kim E.-J., Young-Gun Y., Woo-Kyeom Y., Young-Soun L., Tae-Young N., In-Kyu L., Mi-Ock L. Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arterioscler. Thromb. Vasc. Biol., 2008, Vol. 28, no. 10, pp. 1796-802. doi: 10.1161/ATVBAHA.108.171546
- Lardone P.J., Guerrero J.M., Fernández-Santos J.M., Rubio A., Martín-Lacave I., Carrillo-Vico A. Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related orphan receptor. J. Pineal Res., 2011, Vol. 51, pp. 454–462. doi: 10.1111/j.1600-079X.2011.00909.x
- Lechtken A., Hörnig M., Werz O., Corvey N., Zündorf I., Dingermann T., Brandes R., Steinhilber D. Extracellular signal-regulated kinase-2 phosphorylates RORα4 in vitro. Biochem. Biophys. Res. Commun., 2007, Vol. 358, no. 3, pp. 890–896. doi: 10.1016/j.bbrc.2007.05.016
- Liu J., Zhou H., Fan W., Dong W., Fu S., He H., Huang F. Melatonin influences proliferation and differentiation of rat dental papilla cells in vitro and dentine formation in vivo by altering mitochondrial activity. J. Pineal Res., 2013, Vol. 54, pp. 170–178. doi: 10.1111/jpi.12002
- Peliciari-Garcia R.A., Zanquetta M.M., Andrade-Silva J., Gomes D.A., Barreto-Chaves M.L., Cipolla-Neto J. Expression of circadian clock and melatonin receptors within cultured rat cardiomyocytes. Chronobiol. Int., 2011, Vol. 28, no. 1, pp. 21-30. doi: 10.3109/07420528.2010.525675
- Rafii-El-Idrissi M., Calvo J.R., Harmouch A., Garcia-Maurino S., Guerrero J.M. Specific binding of melatonin by purified cell nuclei from spleen and thymus of the rat. J. Neuroimmunol., 1998, Vol. 86, pp. 190-197. doi: 10.1016/s0165-5728(98)00048-4
- Sato T.K., Panda S., Miraglia L.J., Reyes T.M., Rudic R.D., McNamara P., Naik K.A., FitzGerald G.A., Kay S.A., Hogenesch J.B. A functional genomics strategy reveals rora as a component of the mammalian circadian clock. Neuron, 2004, Vol. 43, pp. 527–537. doi: 10.1016/j.neuron.2004.07.018
- Shah S.A., Khan M., Jo M.H., Jo M.G., Amin F.U., Kim M.O. Melatonin stimulates the SIRT1/Nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci. Ther., 2017, Vol. 23, pp. 33–44. doi: 10.1111/cns.12588
- Slominski A.T., Kim T.K., Takeda Y., Janjetovic Z., Brozyna A.A., Skobowiat C., Wang J., Postlethwaite A., Li W., Tuckey R.C. RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J., 2014, Vol. 28, pp. 2775–2789. doi: 10.1096/fj.13-242040
- Solt L.A., Griffin P.R., Burris T.P. Ligand regulation of retinoic acid receptor-related orphan receptors: Implications for development of novel therapeutics. Curr. Opin. Lipidol., 2010, Vol. 21, pp. 204–211. doi: 10.1097/MOL.0b013e328338ca18
- Talevi A. Computer-Aided Drug Design: An Overview. Methods Mol. Biol., 2018, Vol. 1762, pp. 1-19. doi: 10.1007/978-1-4939-7756-7_1
- Wiesenberg I., Missbach M., Kahlen J.P., Schräder M., Carlberg C. Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acids Res., 1995, Vol. 23, pp. 327–333. doi: 10.1093/nar/23.3.327
- Yang X.O., Pappu B.P., Nurieva R., Akimzhanov A., Kang H.S., Chung Y., Ma L., Shah B., Panopoulos A.D., Schluns K.S., Watowich S.S., Tian Q., Jetten A.M., Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity, 2008, Vol. 28, pp. 29–39. doi: 10.1016/j.immuni.2007.11.016
- Zang M., Zhao Y., Gao L., Zhong F., Qin Z., Tong R., Ai L., Petersen L., Yan Y., Gao Y. The circadian nuclear receptor RORα negatively regulates cerebral ischemia–reperfusion injury and mediates the neuroprotective effects of melatonin. BBA Mol. Basis Dis., 2020, Vol. 1866, 165890. doi: 10.1016/j.bbadis.2020.165890
- Zhao L., A. R., Yang Y., Yang X., Liu H., Yue L., Li X., Lin Y., Reiter R.J., Qu Y. Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: The role of SIRT1 signaling. J. Pineal Res., 2015, Vol. 59, pp. 230–239. doi: 10.1111/jpi.12254
- 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-α in diabetic cardiomyopathy. J. Pineal Res., 2017, Vol. 62, no. 3, e12378. doi: 10.1111/jpi.12378