Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Repurposing Auranofin, an Anti-Rheumatic Gold Compound, to Treat Acne Vulgaris by Targeting the NLRP3 Inflammasome

  • Yang, Gabsik (BK21plus Team, College of Pharmacy, The Catholic University of Korea) ;
  • Lee, Seon Joo (BK21plus Team, College of Pharmacy, The Catholic University of Korea) ;
  • Kang, Han Chang (BK21plus Team, College of Pharmacy, The Catholic University of Korea) ;
  • Cho, Yong-Yeon (BK21plus Team, College of Pharmacy, The Catholic University of Korea) ;
  • Lee, Hye Suk (BK21plus Team, College of Pharmacy, The Catholic University of Korea) ;
  • Zouboulis, Christos C. (Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Brandenburg Medical School Theodore Fontane) ;
  • Han, Sin-Hee (Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration) ;
  • Ma, Kyung-Ho (Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration) ;
  • Jang, Jae-Ki (Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration) ;
  • Lee, Joo Young (BK21plus Team, College of Pharmacy, The Catholic University of Korea)
  • Received : 2020.01.13
  • Accepted : 2020.03.31
  • Published : 2020.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Activation of the NLRP3 inflammasome is critical for host defense as well as the progression of inflammatory diseases through the production of the proinflammatory cytokine IL-1β, which is cleaved by active caspase-1. It has been reported that overactivation of the NLRP3 inflammasome contributes to the development and pathology of acne vulgaris. Therefore, inhibiting activation of the NLRP3 inflammasome may provide a new therapeutic strategy for acne vulgaris. In this study, we investigated whether auranofin, an anti-rheumatoid arthritis agent, inhibited NLRP3 inflammasome activation, thereby effectively treating acne vulgaris. Auranofin suppressed NLRP3 inflammasome activation induced by Propionibacterium acnes, reducing the production of IL-1β in primary mouse macrophages and human sebocytes. In a P. acnes-induced acne mouse model, injection of P. acnes into the ears of mice induced acne symptoms such as redness, swelling, and neutrophil infiltration. Topical application of auranofin (0.5 or 1%) to mouse ears significantly reduced the inflammatory symptoms of acne vulgaris induced by P. acnes injection. Topical application of auranofin led to the downregulation of the NLRP3 inflammasome activated by P. acnes in mouse ear skin. These results show that auranofin inhibits the NLRP3 inflammasome, the activation of which is associated with acne symptoms. The results further suggest that topical application of auranofin could be a new therapeutic strategy for treating acne vulgaris by targeting the NLRP3 inflammasome.

Keywords

References

  1. Blocka, K. L., Paulus, H. E. and Furst, D. E. (1986) Clinical pharmacokinetics of oral and injectable gold compounds. Clin. Pharmacokinet. 11, 133-143. https://doi.org/10.2165/00003088-198611020-00003
  2. Dalziel, K., Going, G., Cartwright, P. H., Marks, R., Beveridge, G. W. and Rowell, N. R. (1986) Treatment of chronic discoid lupus erythematosus with an oral gold compound (auranofin). Br. J. Dermatol. 115, 211-216. https://doi.org/10.1111/j.1365-2133.1986.tb05720.x
  3. Dispenza, M. C., Wolpert, E. B., Gilliland, K. L., Dai, J. P., Cong, Z., Nelson, A. M. and Thiboutot, D. M. (2012) Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients. J. Invest. Dermatol. 132, 2198-2205. https://doi.org/10.1038/jid.2012.111
  4. Gollnick, H. and Schramm, M. (1998) Topical drug treatment in acne. Dermatology 196, 119-125. https://doi.org/10.1159/000017844
  5. Goodfield, M. J., Cox, N. H., Bowser, A., McMillan, J. C., Millard, L. G., Simpson, N. B. and Ormerod, A. D. (2010) Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. 2010. Br. J. Dermatol. 162, 1172-1179. https://doi.org/10.1111/j.1365-2133.2010.09836.x
  6. Guo, H., Callaway, J. B. and Ting, J. P. (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677-687. https://doi.org/10.1038/nm.3893
  7. Helm, K. F., Marks, J. G., Jr., Leyden, J. J., Guzzo, C., Krueger, G. G., Griffiths, T. W. and Griffiths, C. E. (1995) Topical auranofin ointment for the treatment of plaque psoriasis. J. Am. Acad. Dermatol. 33, 517-519. https://doi.org/10.1016/0190-9622(95)91402-1
  8. Jeremy, A. H., Holland, D. B., Roberts, S. G., Thomson, K. F. and Cunliffe, W. J. (2003) Inflammatory events are involved in acne lesion initiation. J. Invest. Dermatol. 121, 20-27. https://doi.org/10.1046/j.1523-1747.2003.12321.x
  9. Jin, M., Hong, Y., Lee, H., Tran, Q., Cho, H., Kim, M., Kwon, S. H., Kang, N. H., Park, J. and Park, J. (2019) 1,2-Dichloropropane (1,2-DCP)-induced angiogenesis in dermatitis. Toxicol. Res. 35, 361-369. https://doi.org/10.5487/TR.2019.35.4.361
  10. Kang, N. J., Han, S. C., Yoon, S. H., Sim, J. Y., Maeng, Y. H., Kang, H. K. and Yoo, E. S. (2019) Cinnamomum camphora leaves alleviate allergic skin inflammatory responses in vitro and in vivo. Toxicol. Res. 35, 279-285. https://doi.org/10.5487/TR.2019.35.3.279
  11. Kistowska, M., Gehrke, S., Jankovic, D., Kerl, K., Fettelschoss, A., Feldmeyer, L., Fenini, G., Kolios, A., Navarini, A., Ganceviciene, R., Schauber, J., Contassot, E. and French, L. E. (2014) IL-1beta drives inflammatory responses to propionibacterium acnes in vitro and in vivo. J. Invest. Dermatol. 134, 677-685. https://doi.org/10.1038/jid.2013.438
  12. Layton, A. (2009) The use of isotretinoin in acne. Dermatoendocrinol. 1, 162-169. https://doi.org/10.4161/derm.1.3.9364
  13. Lee, H. E., Lee, J. Y., Yang, G., Kang, H. C., Cho, Y. Y., Lee, H. S. and Lee, J. Y. (2019a) Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells. Sci. Rep. 9, 12277.
  14. Lee, H. E., Yang, G., Park, Y. B., Kang, H. C., Cho, Y. Y., Lee, H. S. and Lee, J. Y. (2019b) Epigallocatechin-3-gallate prevents acute gout by suppressing NLRP3 inflammasome activation and mitochondrial DNA synthesis. Molecules 24, E2138. https://doi.org/10.3390/molecules24112138
  15. Li, Z. J., Choi, D. K., Sohn, K. C., Seo, M. S., Lee, H. E., Lee, Y., Seo, Y. J., Lee, Y. H., Shi, G., Zouboulis, C. C., Kim, C. D., Lee, J. H. and Im, M. (2014) Propionibacterium acnes activates the NLRP3 inflammasome in human sebocytes. J. Invest. Dermatol. 134, 2747-2756. https://doi.org/10.1038/jid.2014.221
  16. Lowenstein, E. B. and Lowenstein, E. J. (2011) Isotretinoin systemic therapy and the shadow cast upon dermatology's downtrodden hero. Clin. Dermatol. 29, 652-661. https://doi.org/10.1016/j.clindermatol.2011.08.026
  17. Madeira, J. M., Bajwa, E., Stuart, M. J., Hashioka, S. and Klegeris, A. (2014) Gold drug auranofin could reduce neuroinflammation by inhibiting microglia cytotoxic secretions and primed respiratory burst. J. Neuroimmunol. 276, 71-79. https://doi.org/10.1016/j.jneuroim.2014.08.615
  18. Marks, J. G., Jr., Helm, K. F., Krueger, G. G., Griffiths, C. E., Guzzo, C. A. and Leyden, J. J. (1995) Contact dermatitis from topical auranofin. J. Am. Acad. Dermatol. 32, 813-814. https://doi.org/10.1016/0190-9622(95)91484-6
  19. Patel, M. N., Carroll, R. G., Galvan-Pena, S., Mills, E. L., Olden, R., Triantafilou, M., Wolf, A. I., Bryant, C. E., Triantafilou, K. and Masters, S. L. (2017) Inflammasome priming in sterile inflammatory disease. Trends Mol. Med. 23, 165-180. https://doi.org/10.1016/j.molmed.2016.12.007
  20. Peck, G. L., Olsen, T. G., Yoder, F. W., Strauss, J. S., Downing, D. T., Pandya, M., Butkus, D. and Arnaud-Battandier, J. (1979) Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N. Engl. J. Med. 300, 329-333. https://doi.org/10.1056/NEJM197902153000701
  21. Qin, M., Pirouz, A., Kim, M. H., Krutzik, S. R., Garban, H. J. and Kim, J. (2014) Propionibacterium acnes Induces IL-1beta secretion via the NLRP3 inflammasome in human monocytes. J. Invest. Dermatol. 134, 381-388. https://doi.org/10.1038/jid.2013.309
  22. Swanson, K. V., Deng, M. and Ting, J. P. (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477-489. https://doi.org/10.1038/s41577-019-0165-0
  23. Thangamani, S., Mohammad, H., Abushahba, M. F., Sobreira, T. J. and Seleem, M. N. (2016) Repurposing auranofin for the treatment of cutaneous staphylococcal infections. Int. J. Antimicrob. Agents 47, 195-201. https://doi.org/10.1016/j.ijantimicag.2015.12.016
  24. Yang, G., Lee, H. E., Yeon, S. H., Kang, H. C., Cho, Y. Y., Lee, H. S., Zouboulis, C. C., Han, S. H., Lee, J. H. and Lee, J. Y. (2018) Licochalcone A attenuates acne symptoms mediated by suppression of NLRP3 inflammasome. Phytother. Res. 32, 2551-2559. https://doi.org/10.1002/ptr.6195
  25. Zouboulis, C. C., Seltmann, H., Neitzel, H. and Orfanos, C. E. (1999) Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J. Invest. Dermatol. 113, 1011-1020. https://doi.org/10.1046/j.1523-1747.1999.00771.x

Cited by

  1. Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections vol.10, pp.1, 2020, https://doi.org/10.3390/antibiotics10010026
  2. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases vol.44, pp.1, 2021, https://doi.org/10.1007/s12272-021-01307-9
  3. Anti-Inflammatory Effect of Auranofin on Palmitic Acid and LPS-Induced Inflammatory Response by Modulating TLR4 and NOX4-Mediated NF-κB Signaling Pathway in RAW264.7 Macrophages vol.22, pp.11, 2021, https://doi.org/10.3390/ijms22115920