Versatile Orphan Nuclear Receptor NR4A2 as a Promising Molecular Target for Multiple Sclerosis and Other Autoimmune Diseases

  • Shinji Oki
  • Benjamin J. E. Raveney
  • Yoshimitsu Doi
  • Takashi Yamamura
Conference paper


The nuclear receptor family is a large group of ligand-dependent or ligand-independent transcription factors with 48 genes identified in the human genome. There is accumulating evidence that nuclear receptors are very fascinating components in terms of biological relevance to human diseases such as cancer, heart diseases, diabetes, and other lifestyle-related diseases or regulatory functions by natural and synthetic ligands. However, because of the multifunctional properties of individual nuclear receptor, the precise molecular behavior of nuclear receptors under physiological circumstances is still far from being completely understood. In addition, nuclear receptors have long been attractive drug targets and provide an enormous body of knowledge about the medicinal chemistry of their small molecule modulators. Importantly, many of the nuclear receptors are druggable targets, which is why numerous natural and synthetic nuclear receptor ligands, mostly composed of the steroid structural class, are on the market. The huge economic impact of those ligands is represented by their estimated share of 10–15% of the global pharmaceutical market. Many nuclear receptors are known as intrinsic components of immune responses including glucocorticoid receptor (GR), retinoic acid receptors (RARs), vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPARs), and retinoid orphan receptors (RORs). Herein, we discuss our recent findings that orphan nuclear receptor NR4A2 is profoundly involved in the development of autoreactive T cells and to be added to the list of beneficial molecular targets for autoimmune diseases such as multiple sclerosis.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Multiple Sclerosis Patient Nuclear Receptor Myelin Oligodendrocyte Glycoprotein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Activation-function 2


Central nervous system


DNA-binding domain


Experimental autoimmune encephalomyelitis






Ligand-binding domain


Myelin basic protein


Major histocompatibility complex


Myelin oligodendrocyte glycoprotein


Multiple sclerosis


NGFI-B response element


Nur-responsive element


Proteolipid protein


Retinoid X receptor


Small interfering RNA


  1. 1.
    Maxwell MA, Muscat GE (2006) The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4:e002PubMedCrossRefGoogle Scholar
  2. 2.
    Aranami T, Yamamura T (2008) Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int 57(2):115–120PubMedCrossRefGoogle Scholar
  3. 3.
    McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8(9):913–919PubMedCrossRefGoogle Scholar
  4. 4.
    Satoh J, Nakanishi M, Koike F, Miyake S, Yamamoto T, Kawai M et al (2005) Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis. Neurobiol Dis 18(3):537–550PubMedCrossRefGoogle Scholar
  5. 5.
    Doi Y, Oki S, Ozawa T, Hohjoh H, Miyake S, Yamamura T (2008) Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines. Proc Natl Acad Sci USA 105(24):8381–8386PubMedCrossRefGoogle Scholar
  6. 6.
    Mattes H (2008) NR4A Subfamily of receptors and thier modulators. In: Ottow E, Weinmann H (eds) Nuclear receptors as drug target. Methods and principles in medicinal chemistry, vol 39. Wiley-VCH, New YorkGoogle Scholar
  7. 7.
    Dubois C, Hengerer B, Mattes H (2006) Identification of a potent agonist of the orphan nuclear receptor Nurr1. ChemMedChem 1(9):955–958PubMedCrossRefGoogle Scholar
  8. 8.
    Hintermann S, Chiesi M, von Krosigk U, Mathe D, Felber R, Hengerer B (2007) Identification of a series of highly potent activators of the Nurr1 signaling pathway. Bioorg Med Chem Lett 17(1):193–196PubMedCrossRefGoogle Scholar
  9. 9.
    Chintharlapalli S, Burghardt R, Papineni S, Ramaiah S, Yoon K, Safe S (2005) Activation of Nur77 by selected 1,1-bis(3′-indolyl)-1-(p-substituted phenyl) methanes induces apoptosis through nuclear pathways. J Biol Chem 280(26):24903–24904PubMedCrossRefGoogle Scholar
  10. 10.
    Morita K, Kawana K, Sodeyama M, Shimomura I, Kagechika H, Makishima M (2005) Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1. Biochem Pharmacol 71(1–2):98–107PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Shinji Oki
    • 1
  • Benjamin J. E. Raveney
    • 1
  • Yoshimitsu Doi
    • 1
  • Takashi Yamamura
    • 1
  1. 1.Department of Immunology, National Institute of NeuroscienceNational Center of Neurology and PsychiatryKodaira, TokyoJapan

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