Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients
A hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a central role in the pathogenesis of AE. Nevertheless, the precise causes of AE-associated barrier dysfunction are largely unknown. In this study, a comprehensive analysis of ceramide composition and lipid organization in nonlesional SC of AE patients and control subjects was performed by means of mass spectrometry, infrared spectroscopy, and X-ray diffraction. In addition, the skin barrier and clinical state of the disease were examined. The level of ceramides with an extreme short chain length is drastically increased in SC of AE patients, which leads to an aberrant lipid organization and a decreased skin barrier function. Changes in SC lipid properties correlate with disease severity but are independent of filaggrin mutations. We demonstrate for the first time that changes in ceramide chain length and lipid organization are directly correlated with the skin barrier defects in nonlesional skin of AE patients. We envisage that these insights will provide a new therapeutic entry in therapy and prevention of AE. A hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a central role in the pathogenesis of AE. Nevertheless, the precise causes of AE-associated barrier dysfunction are largely unknown. In this study, a comprehensive analysis of ceramide composition and lipid organization in nonlesional SC of AE patients and control subjects was performed by means of mass spectrometry, infrared spectroscopy, and X-ray diffraction. In addition, the skin barrier and clinical state of the disease were examined. The level of ceramides with an extreme short chain length is drastically increased in SC of AE patients, which leads to an aberrant lipid organization and a decreased skin barrier function. Changes in SC lipid properties correlate with disease severity but are independent of filaggrin mutations. We demonstrate for the first time that changes in ceramide chain length and lipid organization are directly correlated with the skin barrier defects in nonlesional skin of AE patients. We envisage that these insights will provide a new therapeutic entry in therapy and prevention of AE. atopic eczema ceramide filaggrin Fourier transform infrared spectroscopy long periodicity phase natural moisturizing factor small angle X-ray diffraction stratum corneum scoring atopic dermatitis short periodicity phase transepidermal water loss The skin offers a protective barrier against allergens, irritants, and microorganisms and prevents excessive transepidermal water loss (TEWL). The barrier function strongly relies on the outermost layer of the skin, the stratum corneum (SC), which consists of corneocytes embedded in a highly organized lipid matrix (1Proksch E. Folster-Holst R. Jensen J.M. Skin barrier function, epidermal proliferation and differentiation in eczema.J. Dermatol. Sci. 2006; 43: 159-169Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 2Elias P.M. Menon G.K. Structural and lipid biochemical correlates of the epidermal permeability barrier.Adv. Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar). This lipid matrix is considered to be important for a proper skin barrier function. Ceramides (CER), cholesterol, and free fatty acids are the main lipid classes in SC. To date, 12 CER subclasses in human SC have been identified with a wide chain length distribution (3Masukawa Y. Narita H. Sato H. Naoe A. Kondo N. Sugai Y. Oba T. Homma R. Ishikawa J. Takagi Y. et al.Comprehensive quantification of ceramide species in human stratum corneum.J. Lipid Res. 2009; 50: 1708-1719Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 4van Smeden J. Hoppel L. van der Heijden R. Hankemeier T. Vreeken R.J. Bouwstra J.A. LC/MS analysis of stratum corneum lipids: ceramide profiling and discovery.J. Lipid Res. 2011; 52: 1211-1221Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). An explanation of the CER nomenclature is given in Fig. 1. The aim of the present study was to determine the chain lengths of each CER subclass in nonlesional skin of atopic eczema (AE) patients and to correlate these with lipid organization, skin barrier function, and disease severity (Fig. 2).Fig. 2Schematic overview of the SC lipid parameters, clinical parameters, and the determinants of the filaggrin content discussed in this article. These parameters may all affect the skin barrier and are therefore investigated in this study. Arrows indicate possible correlations that are discussed.View Large Image Figure ViewerDownload Hi-res image Download (PPT) AE is a chronic relapsing inflammatory skin disease characterized by a broad spectrum of clinical manifestations, such as erythema, dryness, and intense pruritus (5Cork M.J. Robinson D.A. Vasilopoulos Y. Ferguson A. Moustafa M. MacGowan A. Duff G.W. Ward S.J. Tazi-Ahnini R. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions.J. Allergy Clin. 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Ceramide and cholesterol composition of the skin of patients with atopic dermatitis.Acta Derm. Venereol. 1998; 78: 27-30Crossref PubMed Scopus (413) Google Scholar–16Elias P.M. Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic Allergy Clin. Immunol. 2009; PubMed Scopus Google Scholar). In has been that AE is strongly with in the filaggrin A. Y. H. A. et of the epidermal barrier protein filaggrin are a factor for atopic 2006; PubMed Scopus Google T. S. M. K. T. of filaggrin in atopic Dermatol. Res. PubMed Scopus Google but the role of for the barrier dysfunction is A. A. A. barrier in atopic eczema and lipid Dermatol. 2011; PubMed Scopus Google T. A. M. M. H. Filaggrin and in skin of patients with atopic dermatitis and 2011; PubMed Scopus Google Scholar). such as in the SC may a role in the decreased skin barrier in AE (12Di Nardo A. Wertz P. Giannetti A. Seidenari S. Ceramide and cholesterol composition of the skin of patients with atopic dermatitis.Acta Derm. Venereol. 1998; 78: 27-30Crossref PubMed Scopus (413) Google Scholar, P.M. corneum an Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar, P.M. M. to in atopic dermatitis.J. Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar). In healthy with of and These are to as the short periodicity phase and long periodicity phase J.A. van der J.A. Structural of human stratum corneum by X-ray Dermatol. 1991; Full Text PDF PubMed Scopus Google Scholar, Wertz of lipid in the of the stratum corneum.J. Dermatol. Full Text PDF PubMed Scopus Google Scholar). A of the lipid organization is in Fig. the lipid the have a organization, a of the be in a organization in stratum corneum PubMed Scopus Google van der H. S. Bouwstra J.A. lipid organization in stratum corneum of patients with atopic dermatitis and Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar). a crucial role in the lipid organization J.A. M. The skin barrier in healthy and 2006; PubMed Scopus Google and have a have changes in CER subclasses in nonlesional SC of AE CER increased CER and long chain and (12Di Nardo A. Wertz P. Giannetti A. Seidenari S. Ceramide and cholesterol composition of the skin of patients with atopic dermatitis.Acta Derm. Venereol. 1998; 78: 27-30Crossref PubMed Scopus (413) Google Scholar, J.M. H. M. H. L. T. S. corneum skin barrier function and filaggrin in patients with atopic PubMed Scopus Google Scholar, J. R. ceramide in by in skin of skin of atopic eczema.J. Dermatol. Full Text Full Text PDF PubMed Scopus Google A. K. Y. M. A. level of ceramides in stratum corneum of atopic dermatitis: an factor in atopic Dermatol. 1991; Full Text PDF PubMed Scopus Google Scholar). of these changes be correlated with changes in skin barrier function. was on the of chain length distribution of on the skin barrier Ishikawa et that lesional skin has a increased level of a chain length of in CER which correlates with the skin barrier function J. Narita H. Kondo N. M. Takagi Y. Y. T. Y. S. S. et in the ceramide of atopic dermatitis Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar). These that CER chain length may be an important factor in skin barrier dysfunction of AE patients. These were the of the present study, in which performed a analysis on CER in on the CER chain length distribution in nonlesional SC of AE patients in relation to lipid organization and skin barrier dysfunction. We SC of nonlesional skin, as to the changes in lipid properties in the of We have identified CER subclasses that an increased level of short in and demonstrate that the level of is increased in AE. The changes in CER chain length distribution correlated with changes in lipid organization, skin barrier function, disease and of natural moisturizing factor of acids, their and Changes in CER chain length distribution correlate with These demonstrate for the first time that CER chain length is an important factor in skin barrier dysfunction in nonlesional skin of AE. The study was in with the of and was by the of the subjects Caucasian subjects and Caucasian AE patients were The of AE patients consists of patients with and patients the of analysis to their for to the study. 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Structural of human stratum corneum by X-ray Dermatol. 1991; Full Text PDF PubMed Scopus Google Scholar). The with CER and CER that changes in these CER affect the on the organization, AE patients a lipid with that correlates strongly with a level of This that CER chain length is an important of the lipid organization in SC. The changes in and organization correlate with the increased and with an skin barrier function in patients with AE. The in this study strongly the in AE patients, a in CER chain length leads to a in lipid organization, which in leads to an barrier function. In addition, the present study that this barrier function is correlated with disease severity as by which is by J. P.M. barrier atopic dermatitis: changes in barrier function provide a of disease Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. T. A. H. severity correlates with barrier in eczema.J. Dermatol. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). This may indicate as a of lipid is nonlesional and the barrier function is are to be for AE A. Y. H. A. et of the epidermal barrier protein filaggrin are a factor for atopic 2006; PubMed Scopus Google an is lipid changes are with the of mutations. We subjects for of the for of the spectrum H. A. S.J. A. K. et spectrum of in atopic dermatitis and J. Dermatol. 2011; PubMed Scopus Google Scholar). In study is that have an on CER composition and lipid In in a study in patients R. P.M. J.M. P. A. et in in epidermal and J. 2011; Full Text Full Text PDF PubMed Scopus Google changes in the organization were the patients and In that the of the patients were with to and was in these patients. In as as in the study, AE patients with P. L. of the stratum corneum 3 filaggrin atopic dermatitis J. Allergy Clin. Scholar, S. P.M. in the filaggrin to level of natural moisturizing factor in the stratum corneum.J. Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar). in this study, changes in correlated with but with the of mutations. This that and and may These may on the Filaggrin with skin and J. 2011; PubMed Scopus Google and which filaggrin P. M. A. L. D.Y. of atopic dermatitis filaggrin skin Allergy Clin. Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar). Changes in are to to a in and with and this may affect in CER (5Cork M.J. Robinson D.A. Vasilopoulos Y. Ferguson A. Moustafa M. MacGowan A. Duff G.W. Ward S.J. Tazi-Ahnini R. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions.J. Allergy Clin. Immunol. 2006; 118 (quiz 22–23): 3-21Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar, R. P.M. J.M. P. A. et in in epidermal and J. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. P.M. by in leads to of lipid and of barrier function and stratum corneum Dermatol. Full Text Full Text PDF PubMed Scopus Google The of the skin and its on the barrier 2006; PubMed Scopus Google the CER composition and lipid the that a the and filaggrin an role in the decreased barrier function of AE patients, the barrier may be This will be of by In in this study, have that the CER chain length is in AE patients by CER and CER These changes correlate with an lipid organization and a decreased barrier function in AE patients. In addition, a was disease severity and in lipid composition and a therapeutic entry to skin barrier defects in AE patients, CER chain length a the SC lipid organization and the skin barrier function of AE patients. The for of the CER and the for for of