Document Type : Original Article

Authors

1 Department of Dermatology, Air Force Medical Center PLA, Beijing 100142, China.

2 Southern Medical District of Chinese PLA General Hospital, Beijing 100853, China.

Abstract

Background: Molecular markers are involved in atopic dermatitis (AD) pathogenesis. The estrogen receptor (ESR)-1 gene, encoding ERα, is reported to express aberrantly in AD patients.
Objective: To detect the biological functions of ESR1 in 2,4 dinitrochlorobenzene (DNCB)-treated mice.
Methods: The DNCB-treated mice received a topical application of emulsion containing the 1,3-bis(4 hydroxyphenyl)-4-methyl-5-[4-(2-piperidinyl ethoxy) phenol]-1H-pyrazole dihydrochloride (MPP; an ESR1-selective antagonist) to dorsal skins and ears. Then the dermatitis scores, histopathological changes, and cytokine levels were evaluated.
Results: MPP specifically downregulated ESR1 expression in DNCB-applied mice. Functionally, application of MPP abolished the DNCB-induced promotion in dermatitis score. Additionally, MPP administration protected against DNCB-induced dermatitis severity, suppressed mast cell infiltration and reduced production of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). Moreover, MPP treatment inhibited DNCB- induced production of Th2 cytokines and infiltration of CD4+ T cells.
Conclusion: ESR1 facilitates Th2-immune response and enhances Th2 cytokines in AD mice.

Keywords

  1. Guttman-Yassky, E., N. Dhingra, and D.Y. Leung, New era of biologic therapeutics in atopic dermatitis. Expert Opin Biol Ther, 2013. 13(4): p. 549-61.
  2. Eichenfield, L.F., et al., Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol, 2014. 70(2): p. 338-51.
  3. Guttman-Yassky, E., K.E. Nograles, and J.G. Krueger, Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts. J Allergy Clin Immunol, 2011. 127(5): p. 1110-8.
  4. Kiebert, G., et al., Atopic dermatitis is associated with a decrement in health-related quality of life. Int J Dermatol, 2002. 41(3): p. 151-8.
  5. Yu, S.H., et al., A systematic review of the safety and efficacy of systemic corticosteroids in atopic dermatitis. J Am Acad Dermatol, 2018. 78(4): p. 733-740.e11.
  6. Saeki, H., et al., Clinical Practice Guidelines for the Management of Atopic Dermatitis 2016. J Dermatol, 2016. 43(10): p. 1117-1145.
  7. Elias, P.M. and M. Steinhoff, "Outside-to-inside" (and now back to "outside") pathogenic mechanisms in atopic dermatitis. J Invest Dermatol, 2008. 128(5): p. 1067-70.
  8. Jung, B.G., et al., Inhibitory effects of interleukin-10 plasmid DNA on the development of atopic dermatitis-like skin lesions in NC/Nga mice. J Vet Sci, 2010. 11(3): p. 213-20.
  9. Herberth, G., et al., Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life. Pediatr Allergy Immunol, 2010. 21(1 Pt 1): p. 5-13.
  10. Chan, L.S., N. Robinson, and L. Xu, Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol, 2001. 117(4): p. 977-83.
  11. Lange, J., et al., High interleukin-13 production by phytohaemagglutinin- and Der p 1-stimulated cord blood mononuclear cells is associated with the subsequent development of atopic dermatitis at the age of 3 years. Clin Exp Allergy, 2003. 33(11): p. 1537-43.
  12. Ohshima, Y., et al., Dysregulation of IL-13 production by cord blood CD4+ T cells is associated with the subsequent development of atopic disease in infants. Pediatr Res, 2002. 51(2): p. 195-200.
  13. Metwally, S.S., et al., IL-13 gene expression in patients with atopic dermatitis: relation to IgE level and to disease severity. Egypt J Immunol, 2004. 11(2): p. 171-7.
  14. Zheng, T., et al., Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol, 2009. 129(3): p. 742-51.
  15. Simon, D., L.R. Braathen, and H.U. Simon, Eosinophils and atopic dermatitis. Allergy, 2004. 59(6): p. 561-70.
  16. Jeong, C.W., et al., Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR. Clin Exp Allergy, 2003. 33(12): p. 1717-24.
  17. Spergel, J.M., et al., Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J Clin Invest, 1999. 103(8): p. 1103-11.
  18. Tsoi, L.C., et al., Atopic Dermatitis Is an IL-13-Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis. J Invest Dermatol, 2019. 139(7): p. 1480-1489.
  19. He, H., et al., Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis. J Allergy Clin Immunol, 2020. 145(6): p. 1615-1628.
  20. Jacob, M., et al., Metabolomics Distinguishes DOCK8 Deficiency from Atopic Dermatitis: Towards a Biomarker Discovery. Metabolites, 2019. 9(11).
  21. Schjødt, M.S., G. Gürdeniz, and B. Chawes, The Metabolomics of Childhood Atopic Diseases: A Comprehensive Pathway-Specific Review. Metabolites, 2020. 10(12).
  22. Pavel, A.B., et al., The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature. J Am Acad Dermatol, 2020. 82(3): p. 690-699.
  23. Yin, S.J., et al., Analysis of the peptides detected in atopic dermatitis and various inflammatory diseases patients-derived sera. Int J Biol Macromol, 2018. 106: p. 1052-1061.
  24. Guclu-Geyik, F., et al., The rs2175898 Polymorphism in the ESR1 Gene has a Significant Sex-Specific Effect on Obesity. Biochem Genet, 2020. 58(6): p. 935-952.
  25. Tan, G.C., et al., The influence of microsatellite polymorphisms in sex steroid receptor genes ESR1, ESR2 and AR on sex differences in brain structure. Neuroimage, 2020. 221: p. 117087.
  26. Acharjee, A., et al., Multi-omics-based identification of atopic dermatitis target genes and their potential associations with metabolites and miRNAs. Am J Transl Res, 2021. 13(12): p. 13697-13709.
  27. Qi, S., et al., Functional Analysis of Estrogen Receptor 1 in Diabetic Wound Healing: A Knockdown Cell-Based and Bioinformatic Study. Med Sci Monit, 2020. 26: p. e928788.
  28. Matsuda, H., et al., Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice. Int Immunol, 1997. 9(3): p. 461-6.
  29. Zhang, E.Y., A.Y. Chen, and B.T. Zhu, Mechanism of dinitrochlorobenzene-induced dermatitis in mice: role of specific antibodies in pathogenesis. PLoS One, 2009. 4(11): p. e7703.
  30. Labouesse, M.A., W. Langhans, and U. Meyer, Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice. Psychopharmacology (Berl), 2015. 232(16): p. 2981-94.
  31. Kang, Y.M., et al., Oleanolic Acid Alleviates Atopic Dermatitis-like Responses In Vivo and In Vitro. Int J Mol Sci, 2021. 22(21).
  32. Song, J.Y., et al., Umbilical cord-derived mesenchymal stem cell extracts ameliorate atopic dermatitis in mice by reducing the T cell responses. Sci Rep, 2019. 9(1): p. 6623.
  33. Livak, K.J. and T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001. 25(4): p. 402-8.
  34. Wang, T., et al., Bioinformatic analysis of key pathways and genes involved in pediatric atopic dermatitis. Biosci Rep, 2021. 41(1).
  35. De Benedetto, A., et al., Histamine and Skin Barrier: Are Histamine Antagonists Useful for the Prevention or Treatment of Atopic Dermatitis? J Clin Med, 2015. 4(4): p. 741-55.
  36. Chen, X., et al., Pseudoephedrine alleviates atopic dermatitis-like inflammatory responses in vivo and in vitro. Life Sci, 2020. 258: p. 118139.
  37. Brunner, P.M., E. Guttman-Yassky, and D.Y. Leung, The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol, 2017. 139(4s): p. S65-s76.
  38. Cephus, J.Y., et al., Estrogen receptor-α signaling increases allergen-induced IL-33 release and airway inflammation. Allergy, 2021. 76(1): p. 255-268.
  39. Pelekanou, V., et al., Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1. J Leukoc Biol, 2016. 99(2): p. 333-47.
  40. Pastore, S., F. Mascia, and G. Girolomoni, The contribution of keratinocytes to the pathogenesis of atopic dermatitis. Eur J Dermatol, 2006. 16(2): p. 125-31.
  41. Park, J.H., et al., Combretum quadrangulare Extract Attenuates Atopic Dermatitis-Like Skin Lesions through Modulation of MAPK Signaling in BALB/c Mice. Molecules, 2020. 25(8).
  42. Dokmeci, E. and C.A. Herrick, The immune system and atopic dermatitis. Semin Cutan Med Surg, 2008. 27(2): p. 138-43.
  43. Jin, H., et al., Animal models of atopic dermatitis. J Invest Dermatol, 2009. 129(1): p. 31-40.
  44. Leung, D.Y. and N.A. Soter, Cellular and immunologic mechanisms in atopic dermatitis. J Am Acad Dermatol, 2001. 44(1 Suppl): p. S1-s12.
  45. Lee, J.W., et al., Pinus densiflora bark extract ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice by regulating Th1/Th2 balance and skin barrier function. Phytother Res, 2018. 32(6): p. 1135-1143.