Atopic Dermatitis – Research Article

Lucas R.a· Szklenar M.b· Mihály J.c· Szegedi A.a· Töröcsik D.a· Rühl R.b,c

Author affiliations

aDepartment of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
bPaprika Bioanalytics BT, Debrecen, Hungary
cDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

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Article / Publication Details

First-Page Preview

Received: August 31, 2021
Accepted: March 27, 2022
Published online: May 24, 2022

Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 0

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM

Abstract

Background: Over the past decade, several controversial studies described a relationship between vitamin D and atopic diseases. Low plasma vitamin D levels or even vitamin D deficiency was associated with an increased incidence of atopic disease, postulating that a higher dietary intake of vitamin D may be a beneficial strategy against atopic diseases such as atopic dermatitis (AD). Objective: Our aim was to determine the relationship between plasma 25-hydroxyvitamin D3 (25(OH)D3) levels, the levels of the ligand of the vitamin D receptor (VDR) heterodimerization partner as well as the retinoid X receptor (RXR) and the active vitamin A5 derivative 9-cis-13,14-dihydroretinoic acid (9CDHRA) and AD severity. Methods/Results: Samples from AD patients (n = 20) and healthy volunteers (n = 20) were assessed. In our study, the frequently measured VDR ligand precursor 25(OH)D3 in addition to the VDR-ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 9CDHRA displayed no different levels when compared with the plasma of AD patients and healthy volunteers. When performing further correlation studies focusing on AD patients, plasma 25(OH)D3 levels showed a negative correlation with eosinophils in blood (EOS) and SCORing Atopic Dermatitis (SCORAD) values, while 1,25(OH)2D3 and 9CDHRA levels correlated positively with plasma IgE, EOS, and SCORAD values. Conclusion: In consequence, the metabolic activation of vitamin D from 25(OH)D3 towards 1,25(OH)2D3 as well as the co-liganding of the RXR by 9CDHRA may be an important signalling mechanism, an important marker for AD development and severity as well as the basis for novel nutritional and pharmaceutical AD treatment options.

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References Leung DY, Jain N, Leo HL. New concepts in the pathogenesis of atopic dermatitis. Curr Opin Immunol. 2003;15(6):634–8. Blunder S, Rühl R, Moosbrugger-Martinz V, Krimmel C, Geisler A, Zhu H, et al. Alterations in epidermal eicosanoid metabolism contribute to inflammation and impaired late differentiation in FLG-mutated atopic dermatitis. J Invest Dermatol. 2017;137(3):706–15. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441–6. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006;118(1):214–9. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337–42. Lucas R, Mihály J, Lowe GM, Graham DL, Szklenar M, Szegedi A, et al. Reduced carotenoid and retinoid concentrations and altered lycopene isomer ratio in plasma of atopic dermatitis patients. Nutrients. 2018;10(10):1390. Torocsik D, Weise C, Gericke J, Szegedi A, Lucas R, Mihaly J, et al. Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non-affected skin of human atopic dermatitis patients. Exp Dermatol. 2019 Feb;28(2):177–189. Mihaly J, Gamlieli A, Worm M, Rühl R. Decreased retinoid concentration and retinoid signalling pathways in human atopic dermatitis. Exp Dermatol. 2011;20(4):326–30. Silverberg NB, Silverberg JI. Inside out or outside in: does atopic dermatitis disrupt barrier function or does disruption of barrier function trigger atopic dermatitis? Cutis. 2015;96(6):359–61. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004;29(12):664–73. Schmuth M, Watson RE, Deplewski D, Dubrac S, Zouboulis CC, Griffiths CE. Nuclear hormone receptors in human skin. Horm Metab Res. 2007;39(2):96–105. Holick MF, Chen TC, Lu Z, Sauter E. Vitamin D and skin physiology: a D-lightful story. J Bone Miner Res. 2007;22(Suppl 2):V28–33. Bergqvist C, Ezzedine K. Vitamin D and the skin: what should a dermatologist know? G Ital Dermatol Venereol. 2019;154(6):669–80. Oren E, Banerji A, Camargo CA Jr. Vitamin D and atopic disorders in an obese population screened for vitamin D deficiency. J Allergy Clin Immunol. 2008;121(2):533–4. Peroni DG, Piacentini GL, Cametti E, Chinellato I, Boner AL. Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children. Br J Dermatol. 2011;164(5):1078–82. Wjst M. The vitamin D slant on allergy. Pediatr Allergy Immunol. 2006;17(7):477–83. Wjst M. Is vitamin D supplementation responsible for the allergy pandemic? Curr Opin Allergy Clin Immunol. 2012;12(3):257–62. Albert PJ, Proal AD, Marshall TG. Vitamin D: the alternative hypothesis. Autoimmun Rev. 2009;8(8):639–44. Costa Silva M, Erotides Silva T, de Alentar ML, Honório Coelho MS, Wildner LM, Bazzo ML, et al. Factors associated with 25-hydroxyvitamin D levels in patients with liver cirrhosis. Ann Hepatol. 2015;14(1):99–107. Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF. Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013;98(3):973–9. Kim MJ, Kim SN, Lee YW, Choe YB, Ahn KJ. Vitamin D status and efficacy of vitamin D supplementation in atopic dermatitis: a systematic review and meta-analysis. Nutrients. 2016;8(12):789. Hattangdi-Haridas SR, Lanham-New SA, Wong WHS, Ho MHK, Darling AL. Vitamin D deficiency and effects of vitamin D supplementation on disease severity in patients with atopic dermatitis: a systematic review and meta-analysis in adults and children. Nutrients. 2019;11(8):1854. Back O, Blomquist HK, Hernell O, Stenberg B. Does vitamin D intake during infancy promote the development of atopic allergy? Acta Derm Venereol. 2009;89(1):28–32. Hypponen E, Berry DJ, Wjst M, Power C. Serum 25-hydroxyvitamin D and IgE: a significant but nonlinear relationship. Allergy. 2009;64(4):613–20. Bikle DD, Chang S, Crumrine D, Elalieh H, Man MQ, Dardenne O, et al. Mice lacking 25OHD 1alpha-hydroxylase demonstrate decreased epidermal differentiation and barrier function. J Steroid Biochem Mol Biol. 2004;89–90(1–5):347–53. Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A. 2006;103(31):11736–41. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A. 1997;94(18):9831–5. Moosbrugger-Martinz V, Schmuth M, Dubrac S. A mouse model for atopic dermatitis using topical application of vitamin D3 or of its analog MC903. Methods Mol Biol. 2017;1559:91–106. Lucas R, Mihály J, Gericke J, Törőcsik D, Rühl R. Vitamin D signaling in a mouse allergic sensitization model. Int J Vitam Nutr Res. 2020;90(5–6):385–8. Lucas R, Mihály J, Gericke J, de Lera AR, Alvarez S, Veleczki Z, et al. Topical vitamin D receptor antagonist/partial-agonist treatment induces epidermal hyperproliferation via RARγ signaling pathways. Dermatology. 2021;237(2):197–203. Hartmann B, Riedel R, Jörss K, Loddenkemper C, Steinmeyer A, Zügel U, et al. Vitamin D receptor activation improves allergen-triggered eczema in mice. J Invest Dermatol. 2012;132(2):330–6. Li XY, Xiao JH, Feng X, Qin L, Voorhees JJ. Retinoid X receptor-specific ligands synergistically upregulate 1, 25-dihydroxyvitamin D3-dependent transcription in epidermal keratinocytes in vitro and in vivo. J Invest Dermatol. 1997;108(4):506–12. Kiss M, Czimmerer Z, Nagy L. The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: from physiology to pathology. J Allergy Clin Immunol. 2013;132(2):264–86. Calleja C, Messaddeq N, Chapellier B, Yang H, Krezel W, Li M, et al. Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes. Genes Dev. 2006;20(11):1525–38. Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, et al. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature. 2000;407(6804):633–6. Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci U S A. 2005;102(41):14795–800. Wolf G. Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr Rev. 2006;64(12):532–8. Rühl R, Krzyzosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L, Vaz B, et al. 9-cis-13,14-dihydroretinoic acid is an endogenous retinoid acting as RXR ligand in mice. PLoS Genet. 2015;11(6):e1005213. de Lera ÁR, Krezel W, Rühl R. An endogenous mammalian retinoid X receptor ligand, at last!. ChemMedChem. 2016;11(10):1027–37. Krezel W, Rivas A, Szklenar M, Ciancia M, Alvarez R, de Lera AR, et al. Vitamin A5/X, a new food to lipid hormone concept for a nutritional ligand to control RXR-mediated signaling. Nutrients. 2021;13(3):925. Rühl R, Krezel W, de Lera AR. 9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5. Nutr Rev. 2018;76(12):929–41. Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European task force on atopic dermatitis. Dermatology. 1993, 186(1):23–31. Mihaly J, Sonntag D, Krebiehl G, Szegedi A, Torocsik D, Rühl R. Steroid concentrations in patients with atopic dermatitis: reduced plasma dehydroepiandrosterone sulfate and increased cortisone levels. Br J Dermatol. 2015;172(1):285–8. Mihaly J, Marosvolgyi T, Szegedi A, Koroskenyi K, Lucas R, Torocsik D, et al. Increased FADS2-derived n-6 PUFAs and reduced n-3 PUFAs in plasma of atopic dermatitis patients. Skin Pharmacol Physiol. 2014;27(5):242–8. Mihaly J, Gericke J, Torocsik D, Gaspar K, Szegedi A, Rühl R. Reduced lipoxygenase and cyclooxygenase mediated signaling in PBMC of atopic dermatitis patients. Prostaglandins Other Lipid Mediat. 2013;107:35–42. Rühl R. Method to determine 4-oxo-retinoic acids, retinoic acids and retinol in serum and cell extracts by liquid chromatography/diode-array detection atmospheric pressure chemical ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006;20(16):2497–504. R-Core-team: a language and environment for statistical computing. R Foundation for statistical computing; 2016. wwwR-projectorg. Cheon BR, Shin JE, Kim YJ, Shim JW, Kim DS, Jung HL, et al. Relationship between serum 25-hydroxyvitamin D and interleukin-31 levels, and the severity of atopic dermatitis in children. Korean J Pediatr. 2015;58(3):96–101. El Taieb MA, Fayed HM, Aly SS, Ibrahim AK. Assessment of serum 25-hydroxyvitamin d levels in children with atopic dermatitis: correlation with SCORAD index. Dermatitis. 2013;24(6):296–301. Amon U, Baier L, Yaguboglu R, Ennis M, Holick MF, Amon J. Serum 25-hydroxyvitamin D levels in patients with skin diseases including psoriasis, infections, and atopic dermatitis. Dermatoendocrinol. 2018;10(1):e1442159. Han TY, Kong TS, Kim MH, Chae JD, Lee JH, Son SJ. Vitamin D status and its association with the SCORAD score and serum LL-37 level in Korean adults and children with atopic dermatitis. Ann Dermatol. 2015;27(1):10–4. Su O, Bahalı AG, Demir AD, Ozkaya DB, Uzuner S, Dizman D, et al. The relationship between severity of disease and vitamin D levels in children with atopic dermatitis. Postepy Dermatol Alergol. 2017;34(3):224–7. Wang SS, Hon KL, Kong AP, Pong HN, Wong GW, Leung TF. Vitamin D deficiency is associated with diagnosis and severity of childhood atopic dermatitis. Pediatr Allergy Immunol. 2014;25(1):30–5. Treptow S, Grun J, Scholz J, Radbruch A, Heine G, Worm M. 9-cis retinoic acid and 1.25-dihydroxyvitamin D3 drive differentiation into IgA(+) secreting plasmablasts in human naive B cells. Eur J Immunol. 2021 Jan;51(1):125–37. Heine G, Hollstein T, Treptow S, Radbruch A, Worm M. 9-cis retinoic acid modulates the type I allergic immune response. J Allergy Clin Immunol. 2017;141(2):650–e5. Brandi ML. Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes. Clin Cases Miner Bone Metab. 2010;7(3):243–50. Stephensen CB, Borowsky AD, Lloyd KC. Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance. Immunology. 2007;121(4):484–98. Du X, Tabeta K, Mann N, Crozat K, Mudd S, Beutler B. An essential role for Rxr alpha in the development of Th2 responses. Eur J Immunol. 2005;35(12):3414–23. Spilianakis CG, Lee GR, Flavell RA. Twisting the Th1/Th2 immune response via the retinoid X receptor: lessons from a genetic approach. Eur J Immunol. 2005;35(12):3400–4. Grenningloh R, Gho A, di Lucia P, Klaus M, Bollag W, Ho IC, et al. Cutting edge: inhibition of the retinoid X receptor (RXR) blocks T helper 2 differentiation and prevents allergic lung inflammation. J Immunol. 2006;176(9):5161–6. Dahten A, Koch C, Ernst D, Schnoller C, Hartmann S, Worm M. Systemic PPARgamma ligation inhibits allergic immune response in the skin. J Invest Dermatol. 2008 Sep;128(9):2211–8. Schmuth M, Moosbrugger-Martinz V, Blunder S, Dubrac S. Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation. Biochim Biophys Acta. 2014;1841(3):463–73. Dubrac S, Schmuth M. PPAR-alpha in cutaneous inflammation. Dermatoendocrinol. 2011;3(1):23–6. Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, et al. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol. 2003;120(2):246–55. Hatano Y, Man MQ, Uchida Y, Crumrine D, Mauro TM, Feingold KR, et al. Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta (but not gamma) and liver X receptor activators. J Allergy Clin Immunol. 2009;125(1):160–9.e1-5. Czarnowicki T, Dohlman AB, Malik K, Antonini D, Bissonnette R, Chan TC, et al. Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: a randomized controlled trial. Ann Allergy Asthma Immunol. 2018;120(6):631–e11. Overbergh L, Stoffels K, Valckx D, Giulietti A, Bouillon R, Mathieu C. Regulation of 25-hydroxyvitamin d-1alpha-hydroxylase by IFNgamma in human monocytic THP1 cells. J Steroid Biochem Mol Biol. 2004;89–90(1–5):453–5. Overbergh L, Stoffels K, Waer M, Verstuyf A, Bouillon R, Mathieu C. Immune regulation of 25-hydroxyvitamin D-1alpha-hydroxylase in human monocytic THP1 cells: mechanisms of interferon-gamma-mediated induction. J Clin Endocrinol Metab. 2006;91(9):3566–74. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–3. Lou YR, Miettinen S, Kagechika H, Gronemeyer H, Tuohimaa P. Retinoic acid via RARalpha inhibits the expression of 24-hydroxylase in human prostate stromal cells. Biochem Biophys Res Commun. 2005;338(4):1973–81. Sakaki T, Sugimoto H, Hayashi K, Yasuda K, Munetsuna E, Kamakura M, et al. Bioconversion of vitamin D to its active form by bacterial or mammalian cytochrome P450. Biochim Biophys Acta. 2010;1814(1):249–56. Beitz R, Mensink GB, Hintzpeter B, Fischer B, Erbersdobler HF. Do users of dietary supplements differ from nonusers in their food consumption? Eur J Epidemiol. 2004;19(4):335–41. Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Scheidt-Nave C. Vitamin D status and health correlates among German adults. Eur J Clin Nutr. 2008;62(9):1079–89. Hintzpeter B, Scheidt-Nave C, Müller MJ, Schenk L, Mensink GB. Higher prevalence of vitamin D deficiency is associated with immigrant background among children and adolescents in Germany. J Nutr. 2008;138(8):1482–90. Rabenberg M, Scheidt-Nave C, Busch MA, Rieckmann N, Hintzpeter B, Mensink GB. Vitamin D status among adults in Germany – results from the German health interview and examination survey for adults (DEGS1). BMC Public Health. 2015;15:641. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science. 1997;277(5333):1827–30. Article / Publication Details

First-Page Preview

Received: August 31, 2021
Accepted: March 27, 2022
Published online: May 24, 2022

Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 0

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM

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