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Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities
Open AccessArticle

Altered Levels of Sphingosine, Sphinganine and Their Ceramides in Atopic Dermatitis Are Related to Skin Barrier Function, Disease Severity and Local Cytokine Milieu

Department of Dermatology and Venereology, University Hospital Center, Zagreb and University of Zagreb School of Medicine, 10000 Zagreb, Croatia
Laboratory for Analytical Chemistry, Department of Chemistry and Biochemistry, Faculty of Food Technology and Biotechnology, University of Zagreb, 10000 Zagreb, Croatia
Amsterdam UMC, University of Amsterdam, Coronel Institute of Occupational Health, Amsterdam Public Health research institute, 1105 AZ Amsterdam, The Netherlands
Laboratory Genetic Metabolic Disease, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(6), 1958;
Received: 19 February 2020 / Revised: 7 March 2020 / Accepted: 9 March 2020 / Published: 13 March 2020
(This article belongs to the Special Issue Skin Epidermis and Barrier Function)
Dysfunctional skin barrier plays a key role in the pathophysiology of atopic dermatitis (AD), a common inflammatory skin disease. Altered composition of ceramides is regarded as a major cause of skin barrier dysfunction, however it is not clear whether these changes are intrinsic or initiated by inflammation and aberrant immune response in AD. This study investigated the levels of free sphingoid bases (SBs) sphingosine and sphinganine and their ceramides and glucosylceramide in the stratum corneum (SC) and related them to skin barrier function, disease severity and local cytokine milieu. Ceramides were measured in healthy skin, and lesional and non-lesional skin of AD patients by a novel method based on deacylation of ceramides which were subsequently determined as corresponding sphingoid bases by using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The cytokine levels were determined by multiplex immunoassay. Atopic skin showed increased levels of most investigated markers, predominantly in lesional skin. The largest difference in respect to healthy skin was found for glucosylceramide with respective median values of 0.23 (IQR 0.18–0.61), 0.56 (IQR 0.32–0.76) and 19.32 (IQR 7.86–27.62) pmol/g protein for healthy, non-lesional and lesional skin. The levels of investigated ceramide markers were correlated with disease severity (scoring atopic dermatitis, SCORAD) and skin barrier function (trans-epidermal water loss, TEWL) and furthermore with cytokines involved in innate, Th-1, and Th-2 immune response. Interestingly, the strongest association with SCORAD was found for sphinganine/sphingosine ratio (r = −0.69, p < 0.001; non-lesional skin), emphasizing the importance of SBs in AD. The highest correlation with TEWL was found for glucosylceramide (r2 = 0.60, p < 0.001), which was investigated for the first time in AD. Findings that the changes in SBs and ceramide levels were predominant in lesional skin and their association with disease severity and cytokine levels suggest an immune-system driven effect. a novel analysis method demonstrates a robust and simple approach that might facilitate wider use of lipid biomarkers in the clinics e.g., to monitor (immune) therapy or dissect disease endotypes. View Full-Text
Keywords: atopic dermatitis; biomarkers; stratum corneum; ceramides; sphingosine; sphinganine atopic dermatitis; biomarkers; stratum corneum; ceramides; sphingosine; sphinganine
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Toncic, R.J.; Jakasa, I.; Hadzavdic, S.L.; Goorden, S.M.; Vlugt, K.J.-V.; Stet, F.S.; Balic, A.; Petkovic, M.; Pavicic, B.; Zuzul, K.; Marinovic, B.; Kezic, S. Altered Levels of Sphingosine, Sphinganine and Their Ceramides in Atopic Dermatitis Are Related to Skin Barrier Function, Disease Severity and Local Cytokine Milieu. Int. J. Mol. Sci. 2020, 21, 1958.

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