SALBUTAMOL AMELIORATES THE PHENOTYPE OF THE SKIN INFLAMMATORY DISEASE PSORIASIS ACCORDING TO SKIN SPHEROID MODELS

Year 2021, Volume: 22 Issue: 2, 187 - 197, 15.10.2021

Özge Sezin Somuncu , Berke Demiriz İrem Türkmen Salih Somuncu Berna Aksoy

https://doi.org/10.23902/trkjnat.878417

Abstract

Psoriasis is a multifactorial chronic inflammatory disorder resulting by the interplay of genetics, the immune system and the environment. It is characterized by the hyperproliferation of epithelial cells, generating red, itchy psoriatic plaques which have no cure but have great negative impact in patients’ life. Although corticosteroids or vitamin D analogs might help recovery to some extent, there is yet no total cure for the disease. In this study, we sought to generate three-dimensional (3D) stress-related psoriatic skin spheroids with the screening of the potential efficacy of a β2-adrenergic receptor agonist, salbutamol. 3D Culture spheroids with human dermal fibroblasts (HDF), human epithelial keratinocytes (HEK) and human monocytic cell line (THP-1) were generated as a representative model of skin and the protocol of stress-related modelling was conducted. The efficacy of the drug salbutamol was evaluated by the changes in mRNA and protein expression levels of selected genes, as well as by several metabolic assays. We developed a method for culturing spherical organoid models of psoriasis in vitro. We tested the potential theurapetic effects of salbutamol on psoriasis spheroids. Spheroids treated with salbutamol indicated the effictiveness of the treatment. 3D spheroid system was found partially efficient for mimicking the physiological features of psoriasis in vitro. This present work may be a starting point for future investigation as it is the first to generate a stress-related psoriatic model and first to try a β2 agonist as a potential treatment option. Considering the effects and suitability of topical application of salbutamol, its efficacy should not be underestimated and should be investigated further for translating this knowledge into clinics.

Keywords

psoriasis, skin spheroids, 3D models, Salbutamol

Thanks

This project used the Bahçeşehir University Faculty of Medicine research laboratories whereat we thank to the Dean of Faculty Türker KILIÇ (İstanbul, Turkey). We also would like to thank Sam Chiappone from Stony Brook University School of Medicine (New York, USA), Department of Pathology for their efforts in proofreading.

References

• 1. Alabi, B.R., LaRanger, R. & Shay, J.W. 2019. Decellularized mice colons as models to study the contribution of the extracellular matrix to cell behavior and colon cancer progression. Acta Biomaterialia, 100: 213-222.
• 2. Armstrong, A., Armstrong, E., Fuller, E., Sockolov, M. & Voyles, S. 2011. Smoking and pathogenesis of psoriasis: a review of oxidative, inflammatory and genetic mechanisms. British Journal of Dermatology, 165(6): 1162-1168.
• 3. Asha, K., Singal, A., Sharma, S.B., Arora, V.K. & Aggarwal, A. 2017. Dyslipidaemia & oxidative stress in patients of psoriasis: Emerging cardiovascular risk factors. Indian Journal of Medical Research, 146: 708-713. https://doi.org/10.4103/ijmr.IJMR_717_16
• 4. Babicki, S., Arndt, D., Marcu, A., Liang, Y.J., Grant, J.R., Maciejewski, A. & Wishart, D.S. 2016. Heatmapper: web-enabled heat mapping for all. Nucleic Acids Research, 44(W1): W147-W153. https://doi.org/10.1093/nar/gkw419
• 5. Bahuguna, A., Khan, I., Bajpai, V.K. & Kang, S.C. 2017. MTT assay to evaluate the cytotoxic potential of a drug. Bangladesh Journal of Pharmacology, 12(2): Online: Apr 8-2017.
• 6. Balak, D.M. & Hajdarbegovic, E. 2017. Drug-induced psoriasis: clinical perspectives. Psoriasis (Auckland, NZ), 7: 87.
• 7. Bosmann, M., Grailer, J.J., Zhu, K., Matthay, M.A., Sarma, J.V., Zetoune, F.S. & Ward, P.A. 2012. Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury. The FASEB Journal, 26(5): 2137-2144.
• 8. Chiricozzi, A., Nograles, K.E., Johnson-Huang, L.M., Fuentes-Duculan, J., Cardinale, I., Bonifacio, K.M., Gulati, N., Mitsui, H., Guttman-Yassky, E. & Suárez-Fariñas, M. 2014. IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model. PloS one, 9(2): e90284. doi:10.1371/journal.pone.0090284
• 9. Desmet, E., Ramadhas, A., Lambert, J. & Van Gele, M. 2017. In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research. Exp Biol Med (Maywood), 242(11): 1158-1169. https://doi.org/10.1177/1535370217710637
• 10. Desmet, E., Ramadhas, A., Lambert, J. & Van Gele, M. 2017. In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research. Experimental biology and medicine, 242(11): 1158-1169.
• 11. Erel, O. 2005. A new automated colorimetric method for measuring total oxidant status. Clinical biochemistry, 38(12): 1103-1111.
• 12. Feliciani, C., Vitullo, P., D'Orazi, G., Palmirotta, R., Amerio, P., Pour, S.M., Coscione, G., Amerio, P.L. & Modesti, A. 1997. The 72-kDa and the 92-kDa gelatinases, but not their inhibitors TIMP-1 and TIMP-2, are expressed in early psoriatic lesions. Exp Dermatol, 6(6): 321-327. doi: 10.1111/j.1600-0625.1997.tb00180.x
• 13. Fujishima, S., Watanabe, H., Kawaguchi, M., Suzuki, T., Matsukura, S., Homma, T., Howell, B.G., Hizawa, N., Mitsuya, T., Huang, S.K. & Iijima, M. 2010. Involvement of IL-17F via the induction of IL-6 in psoriasis. Arch Dermatol Res, 302(7): 499-505. https://doi.org/10.1007/s00403-010-1033-8
• 14. Ghanemi, A. & St-Arnand, J. 2018. Interleukin-6 as a "metabolic hormone". Cytokine, 112: 132-136. https://doi.org/10.1016/j.cyto.2018.06.034
• 15. Glazewska, E.K., Niczyporuk, M., Lawicki, S., Szmitkowski, M., Zajkowska, M., Bedkowska, G.E. & Przylipiak, A. 2016. Therapy of psoriasis with narrowband ultraviolet-B light influences plasma concentrations of MMP-2 and TIMP-2 in patients. Ther Clin Risk Manag, 12: 1579-1585. https://doi.org/10.2147/TCRM.S113769
• 16. Glowacka, E., Lewkowicz, P., Rotsztejn, H. & Zalewska, A. 2010. IL-8, IL-12 and IL-10 cytokines generation by neutrophils, fibroblasts and neutrophils- fibroblasts interaction in psoriasis. Adv Med Sci, 55(2): 254-260. https://doi.org/10.2478/v10039-010-0037-0
• 17. Gutowska‐Owsiak, D., Schaupp, A.L., Salimi, M., Selvakumar, T.A., McPherson, T., Taylor, S. & Ogg, G.S. 2012. IL‐17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. Experimental dermatology, 21(2): 104-110.
• 18. Hawkes, J.E., Chan, T.C. & Krueger, J.G. 2017. Psoriasis pathogenesis and the development of novel targeted immune therapies. Journal of Allergy and Clinical Immunology, 140(3): 645-653.
• 19. Ivascu, A. & Kubbies, M. 2006. Rapid generation of single-tumor spheroids for high-throughput cell function and toxicity analysis. Journal of biomolecular screening, 11(8): 922-932.
• 20. Jovanovic, D.V., Martel‐Pelletier, J., Di Battista, J.A., Mineau, F., Jolicoeur, F.C., Benderdour, M. & Pelletier, J.P. 2000. Stimulation of 92‐kd gelatinase (matrix metalloproteinase 9) production by interleukin‐17 in human monocyte/macrophages: A possible role in rheumatoid arthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 43(5): 1134-1144.
• 21. Keränen, T., Hömmö, T., Moilanen, E. & Korhonen, R. 2017. β2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages. Cytokine, 94: 1-7.
• 22. Klicks, J., von Molitor, E., Ertongur-Fauth, T., Rudolf, R. & Hafner, M. 2017. In vitro skin three-dimensional models and their applications. Journal of Cellular Biotechnology, 3(1): 21-39.
• 23. Lin, X. & Huang, T. 2016. Oxidative stress in psoriasis and potential therapeutic use of antioxidants. Free radical research, 50(6): 585-595.
• 24. Liu, F., Wang, S.P., Liu, B., Wang, Y.K. & Tan, W. 2020. (R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism. Cells, 9(2). https://doi.org/10.3390/cells9020511
• 25. Makino, T., Mizawa, M., Yamakoshi, T., Takaishi, M. & Shimizu, T. 2014. Expression of filaggrin-2 protein in the epidermis of human skin diseases: a comparative analysis with filaggrin. Biochem Biophys Res Commun, 449(1): 100-106. https://doi.org/10.1016/j.bbrc.2014.04.165
• 26. Makino, T., Mizawa, M., Yamakoshi, T., Takaishi, M. & Shimizu, T. 2014. Expression of filaggrin-2 protein in the epidermis of human skin diseases: a comparative analysis with filaggrin. Biochemical and biophysical research communications, 449(1): 100-106.
• 27. Miller, N.J., Rice-Evans, C., Davies, M.J., Gopinathan, V. & Milner, A. 1993. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clinical science, 84(4): 407-412.
• 28. Ogawa, E., Sato, Y., Minagawa, A. & Okuyama, R. 2018. Pathogenesis of psoriasis and development of treatment. The Journal of dermatology, 45(3): 264-272.
• 29. Peluso, I., Cavaliere, A. & Palmery, M. 2016. Plasma total antioxidant capacity and peroxidation biomarkers in psoriasis. Journal of biomedical science, 23(1): 52.
• 30. Pullar, C.E. & Isseroff, R.R. 2006. The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. Journal of cell science, 119(3): 592-602.
• 31. Sharma, M., Levenson, C., Clements, I., Castella, P., Gebauer, K. & Cox, M.E. 2017. East Indian sandalwood oil (EISO) alleviates inflammatory and proliferative pathologies of psoriasis. Frontiers in pharmacology, 8: 125.
• 32. Simonsen, S., Thyssen, J.P., Heegaard, S., Kezic, S. & Skov, L. 2017. Expression of filaggrin and its degradation products in human skin following erythemal doses of ultraviolet B irradiation. Acta dermato-venereologica, 97(6-7): 797-801.
• 33. Sivamani, R.K., Lam, S.T. & Isseroff, R.R. 2007. Beta adrenergic receptors in keratinocytes. Dermatologic clinics, 25(4): 643-653.
• 34. Somuncu, Ö.S., Coşkun, Y., Ballica, B., Temiz, A.F. & Somuncu, D. 2019. In vitro artificial skin engineering by decellularized placental scaffold for secondary skin problems of meningomyelocele. Journal of Clinical Neuroscience, 59: 291-297.
• 35. Somuncu, Ö.S., Taşlı, P.N., Şişli, H.B., Somuncu, S. & Şahin, F. 2015. Characterization and differentiation of stem cells isolated from human newborn foreskin tissue. Applied biochemistry and biotechnology, 177(5): 1040-1054.
• 36. Somuncu, S., Somuncu, Ö.S., Ballıca, B. & Tabandeh, B. 2019. Deficiency of Epithelial–Mesenchymal Transition Causes Child Indirect Inguinal Hernia. Journal of pediatric surgery, 55(4):665-671. doi: 10.1016/j.jpedsurg.2019.06.020
• 37. Starodubtseva, N.L., Sobolev, V.V., Soboleva, A.G., Nikolaev, A.A. & Bruskin, S.A. 2011. [Expression of genes for metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-12) associated with psoriasis]. Genetika, 47(9): 1254-1261.
• 38. Steinkraus, V., Steinfath, M., Stöve, L., Körner, C., Abeck, D. & Mensing, H. 1993. β-adrenergic receptors in psoriasis: evidence for down-regulation in lesional skin. Archives of dermatological research, 285(5): 300-304.
• 39. Sun, W., Liu, D.-B., Li, W.-W., Zhang, L.-L., Long, G.-X., Wang, J.-F., Mei, Q. & Hu, G.-Q. 2014. Interleukin-6 promotes the migration and invasion of nasopharyngeal carcinoma cell lines and upregulates the expression of MMP-2 and MMP-9. International journal of oncology, 44(5): 1551-1560.
• 40. Takematsu, H. & Tagami, H. 1990. Granulocyte-macrophage colony-stimulating factor in psoriasis. Dermatology, 181(1): 16-20.
• 41. Takeshita, J., Grewal, S., Langan, S.M., Mehta, N.N., Ogdie, A., Van Voorhees, A.S. & Gelfand, J.M. 2017. Psoriasis and comorbid diseases: Epidemiology. J Am Acad Dermatol, 76(3): 377-390. https://doi.org/10.1016/j.jaad.2016.07.064
• 42. Thewes, M.s., Stadler, R., Korge, B. & Mischke, D. 1991. Normal psoriatic epidermis expression of hyperproliferation-associated keratins. Archives of dermatological research, 283(7): 465-471.
• 43. Torsekar, R. & Gautam, M.M. 2017. Topical therapies in psoriasis. Indian dermatology online journal, 8(4): 235.
• 44. Vörsmann, H., Groeber, F., Walles, H., Busch, S., Beissert, S., Walczak, H. & Kulms, D. 2013. Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing. Cell death & disease, 4(7): e719-e719.
• 45. Waseem, A., Alam, Y., Lalli, A., Dogan, B., Tidman, N., Purkis, P., Jackson, S., Machesney, M. & Leigh, I.M. 1999. Keratin 15 expression in stratified epithelia: downregulation in activated keratinocytes. Journal of Investigative Dermatology, 112(3): 362-369.
• 46. Weatherhead, S.C., Farr, P.M., Jamieson, D., Hallinan, J.S., Lloyd, J.J., Wipat, A. & Reynolds, N.J. 2011. Keratinocyte apoptosis in epidermal remodeling and clearance of psoriasis induced by UV radiation. Journal of Investigative Dermatology, 131(9): 1916-1926.