Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

The selective retinoic acid receptor-α agonist AM580 fails to control autoimmune neuroinflammation

Cellular & Molecular Immunology volume 16, pages 727–729 (2019)Cite this article

Subjects

Environmental cues provided by products from the diet, gut microbiota metabolism, and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome of multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS),1 which affects approximately 2.3 million people worldwide.2 Among these receptors, the ligand-activated transcription factor retinoic acid receptor α (RAR-α) senses retinoic acid and other ligands to promote the transcription of genes that have retinoic acid receptor elements in their promoter region.3 Supplementation with all-trans retinoic acid (ATRA), a metabolite of vitamin A, ameliorates inflammation in MS and the corresponding animal model, experimental autoimmune encephalomyelitis (EAE), by shifting the balance between Th17/regulatory T cells (Tregs) and inducing tolerogenic dendritic cells.4,5 To overcome the weaknesses associated with ATRA agonists, e.g., instability, poor bioavailability and nonselective binding to a broad range of retinoid receptors, a variety of synthetic agonists specifically targeting RAR have been developed.6 One of them, AM80, inhibits Th17 cells and suppress acute neuroinflammation; however, continuous AM80 treatment is ineffective, most likely because AM80 also inhibits Tregs and IL-10 production.6 AM580, a stable benzoic derivative of retinoic acid and a selective RAR-α agonist, has been recently shown to significantly reduce the production of Th1 cytokines but promote Th2 cytokines in human PBMCs7 and to inhibit microglial activation, thus acting beneficially in Alzheimer’s disease treatment.8 In addition, AM580 protects retinal cells against diabetes-induced apoptosis by inducing neurotrophic factors.9 However, whether it has a protective effect on neuroinflammation is unknown.

IFN-γ-producing Th1 and IL-17-producing Th17 cells are major drivers of CNS inflammation and promote damage to myelin sheaths.10 We thus investigated whether the ineffectiveness of AM580 in suppressing EAE development was due to the failure of AM580 to modulate either or both of these encephalitogenic T cell populations. Mononuclear cells were harvested from the CNS and spleen of EAE mice at day 21 p.i., and IFN-γ and IL-17 production within the gated CD4+ T cell population was analyzed. We found that AM580 did not produce significant changes in the cells that produced these cytokines (Fig. 1e). No significant difference was observed for Foxp3 expression or IL-10 production in CD4+ T cells between the AM580- and vehicle-treated mice (data not shown). Collectively, our results show that the RAR-α agonist AM580 is ineffective in suppressing CNS inflammation and EAE development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    Article  CAS  Google Scholar 

  2. Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B. & Ciccarelli, O. Multiple sclerosis. Lancet 391, 1622–1636 (2018).

    Article  Google Scholar 

  3. di Masi, A. et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol. Asp. Med 41, 1–115 (2015).

    Article  Google Scholar 

  4. Harrirchian, M. H. et al. The effect of vitamin A supplementation on disease progression, cytokine levels and gene expression in multiple sclerotic patients: study protocol for a randomized controlled trial. Acta Med Iran. 52, 94–100 (2014).

    CAS  PubMed  Google Scholar 

  5. Racke, M. K. et al. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J. Immunol. 154, 450–458 (1995).

    CAS  PubMed  Google Scholar 

  6. Klemann, C. et al. Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am. J. Pathol. 174, 2234–2245 (2009).

    Article  CAS  Google Scholar 

  7. Gianni, M. et al. AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. Blood 87, 1520–1531 (1996).

    CAS  PubMed  Google Scholar 

  8. Goncalves, M. B. et al. Amyloid beta inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor alpha agonist. Eur. J. Neurosci. 37, 1182–1192 (2013).

    Article  Google Scholar 

  9. Nishikiori, N. et al. Experimental effect of retinoic acids on apoptosis during the development of diabetic retinopathy. Clin. Ophthalmol. 2, 233–235 (2008).

    Article  Google Scholar 

  10. Kaskow B. J., Baecher-Allan C. Effector T cells in multiple sclerosis. Cold. Spring. Harb. Perspect. Med. 8, pii: a029025 (2018)

Download references

Acknowledgements

This work was supported by the NIH grants NS099594 and AI135601. Q.W. and C.G.M. were supported by grants from the National Natural Science Foundation of China (No. 81371414 and 81473577). The authors thank Katherine Regan for her editorial assistance.

Author information

Authors and Affiliations

  1. Department of Neurology, Thomas Jefferson University, 900 Walnut Street, Suite 300, Philadelphia, PA, 19107, USA

    Qing Wang, Rodolfo Thome, Abdolmohamad Rostami & Guang-Xian Zhang

  2. The Key Research Laboratory for the Study of Beneficial Qi and the Blood Circulation Activation Method in Treating Multiple Sclerosis, State Administration of Traditional Chinese Medicine, Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, 030024, China

    Qing Wang & Cun-Gen Ma

Authors
  1. Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rodolfo Thome
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdolmohamad Rostami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cun-Gen Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guang-Xian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Cun-Gen Ma or Guang-Xian Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Thome, R., Rostami, A. et al. The selective retinoic acid receptor-α agonist AM580 fails to control autoimmune neuroinflammation. Cell Mol Immunol 16, 727–729 (2019). https://doi.org/10.1038/s41423-019-0238-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0238-9

Search

Advanced search

Quick links