Ceramides in the skin barrier

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Abstract

The skin barrier, which is essential for human survival on dry land, is located in the uppermost skin layer, the stratum corneum. The stratum corneum consists of corneocytes surrounded by multilamellar lipid membranes that prevent excessive water loss from the body and entrance of undesired substances from the environment. To ensure this protective function, the composition and organization of the lipid membranes is highly specialized. The major skin barrier lipids are ceramides, fatty acids and cholesterol in an approximately equimolar ratio. With hundreds of molecular species of ceramide, skin barrier lipids are a highly complex mixture that complicate the investigation of its behaviour. In this minireview, the structures of the major skin barrier lipids, formation of the stratum corneum lipid membranes and their molecular organization are described.

References

  • [1] Banks-Schlegel S, Green H. Involucrin synthesis and tissue assembly by keratinocytes in natural and cultured human epithelia. J Cell Biol. 1981;90:732-737.

  • [2] Behne M, Uchida Y, Seki T, de Montellano PO, Elias PM, Holleran WM. J. Invest. Dermatol. 2000;114:185.

  • [3] Bouwstra JA, Gooris GS, Bras W, Downing DT. Lipid organization in pig stratum corneum. J. Lipid. Res. 1995;36:685-695.

  • [4] Bouwstra JA, Gooris GS, Dubbelaar FE, Ponec M. Phase behavior of lipid mixtures based on human ceramides: coexistence of crystalline and liquid phases. J. Lipid. Res. 2001;42:1759-1770.

  • [5] Bouwstra JA, Gooris GS, van der Spek JA, Bras W. Structural investigations of human stratum corneum by small-angle X-ray scattering. J. Invest. Dermatol. 1991;97:1005-1012.

  • [6] Bouwstra JA, Ponec M. The skin barrier in healthy and diseased state. Biochim. Biophys. Acta. 2006;1758:2080-2095.

  • [7] Breathnach AS. Aspects of epidermal ultrastructure. J. Invest. Dermatol. 1975;65:2-15.

  • [8] Breiden B, Sandhoff K. The role of sphingolipid metabolism in cutaneous permeabilitybarrier formation. Biochim Biophys Acta. 2014;1841:441-452.

  • [9] Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 2005;6:328-340.

  • [10] Corkery RW. The anti-parallel, extended or splayed-chain conformation of amphiphilic lipids. Colloids Surf B Biointerfaces. 2002;26:3-20.

  • [11] Craven B. Pseudosymmetry in cholesterol monohydrate. Acta Crystallogr Sect B. 1979;35:1123-1128.

  • [12] Damien F, Boncheva M. The extent of orthorhombic lipid phases in the stratum corneum determines the barrier efficiency of human skin in vivo. J. Invest. Dermatol. 2010;130:611-614.

  • [13] de Jager M, Gooris G, Ponec M, Bouwstra J. Acylceramide head group architecture affects lipid organization in synthetic ceramide mixtures. J. Invest. Dermatol. 2004;123:911-916.

  • [14] de Jager M, Groenink W, i Guivernau RB, et al. A novel in vitro percutaneous penetration model: evaluation of barrier properties with p-aminobenzoic acid and two of its derivatives. Pharmaceut. Res. 2006;23:951-960.

  • [15] de Sousa Neto D, Gooris G, Bouwstra J. Effect of the omega-acylceramides on the lipid organization of stratum corneum model membranes evaluated by X-ray diffraction and FTIR studies (Part I). Chem Phys Lipids. 2011;164:184-195.

  • [16] Elias PM. Skin barrier function. Curr. Allergy Asthma Rep. 2008;8:299-305.

  • [17] Elias PM, Goerke J, Friend DS. Mammalian Epidermal Barrier Layer Lipids: Composition and Influence on Structure. J. Invest. Dermatol. 1977;69:535-546.

  • [18] Elias PM, Gruber R, Crumrine D, et al. Formation and functions of the corneocyte lipid envelope (CLE). Biochim Biophys Acta. 2014;1841:314-318.

  • [19] Feingold KR, Elias PM. Role of lipids in the formation and maintenance of the cutaneous permeability barrier. Biochim. Biophys. Acta. 2014;1841:280-294.

  • [20] Grayson S, Elias PM. Isolation and Lipid Biochemical Characterization of Stratum Corneum Membrane Complexes: Implications for the Cutaneous Permeability Barrier. J. Invest. Dermatol. 1982;78:128-135.

  • [21] Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science. 1996;274:1855-1859.

  • [22] Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 2008;9:139-150.

  • [23] Holleran WM, Takagi Y, Uchida Y. Epidermal sphingolipids: metabolism, function, and roles in skin disorders. FEBS Lett. 2006;580:5456-5466.

  • [24] Hou SY, Mitra AK, White SH, Menon GK, Ghadially R, Elias PM. Membrane structures in normal and essential fatty acid-deficient stratum corneum: characterization by ruthenium tetroxide staining and x-ray diffraction. J. Invest. Dermatol. 1991;96:215-223.

  • [25] Iwai I, Han H, den Hollander L, et al. The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. J. Invest. Dermatol. 2012;132:2215-2225.

  • [26] Jakasa I, Koster ES, Calkoen F, et al. Skin barrier function in healthy subjects and patients with atopic dermatitis in relation to filaggrin loss-of-function mutations. J. Invest. Dermatol. 2011;131:540-542.

  • [27] Janusova B, Zbytovska J, Lorenc P, et al. Effect of ceramide acyl chain length on skin permeability and thermotropic phase behavior of model stratum corneum lipid membranes. Biochim Biophys Acta. 2011;1811:129-137.

  • [28] Janůšova B, Zbytovska J, Lorenc P, et al. Effect of ceramide acyl chain length on skin permeability and thermotropic phase behavior of model stratum corneum lipid membranes. BBA-Mol. Cell Biol. L. 2011;1811:129-137.

  • [29] Jennemann R, Rabionet M, Gorgas K, et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet. 2012;21:586-608.

  • [30] Jensen JM, Schutze S, Forl M, Kronke M, Proksch E. Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. J. Clin. Invest. 1999;104:1761-1770.

  • [31] Jungersted JM, Scheer H, Mempel M, et al. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy. 2010;65:911-918.

  • [32] Kessner D, Brezesinski G, Funari SS, Dobner B, Neubert RH. Impact of the long chain omega-acylceramides on the stratum corneum lipid nanostructure. Part 1: Thermotropic phase behaviour of CER[EOS] and CER[EOP] studied using X-ray powder diffraction and FT-Raman spectroscopy. Chem Phys Lipids. 2010;163:42-50.

  • [33] Kessner D, Ruettinger A, Kiselev MA, Wartewig S, Neubert RH. Properties of ceramides and their impact on the stratum corneum structure. Part 2: stratum corneum lipid model systems. Skin Pharmacol. Physiol. 2008;21:58-74.

  • [34] Kovacik A, Opalka L, Silarova M, Roh J, Vavrova K. Synthesis of 6-hydroxyceramide using ruthenium-catalyzed hydrosilylation- -protodesilylation. Unexpected formation of a long periodicity lamellar phase in skin lipid membranes. RSC Adv. 2016;6:73343-73350.

  • [35] Kovačik A, Roh J, Vavrova K. The chemistry and biology of 6 hydroxyceramide, the youngest member of the human sphingolipid family. ChemBioChem. 2014;15:1555-1562.

  • [36] Lampe MA, Burlingame A, Whitney J, et al. Human stratum corneum lipids: characterization and regional variations. J.Lipid Res. 1983;24:120-130.

  • [37] Long SA, Wertz PW, Strauss JS, Downing DT. Human stratum corneum polar lipids and desquamation. Arch Dermatol Res. 1985;277:284-287.

  • [38] Madison KC, Swartzendruber DC, Wertz PW, Downing DT. Presence of intact intercellular lipid lamellae in the upper layers of the stratum corneum. J. Invest. Dermatol. 1987;88:714-718.

  • [39] Masukawa Y, Narita H, Shimizu E, et al. Characterization of overall ceramide species in human stratum corneum. J. Lipid. Res. 2008;49:1466-1476.

  • [40] Mendelsohn R, Flach CR, Moore DJ. Determination of molecular conformation and permeation in skin via IR spectroscopy, microscopy, and imaging. Biochim Biophys Acta. 2006;1758:923-933.

  • [41] Mendelsohn R, Moore DJ. Infrared determination of conformational order and phase behavior in ceramides and stratum corneum models. Methods Enzymol. 2000;312:228-247.

  • [42] Mizutani Y, Mitsutake S, Tsuji K, Kihara A, Igarashi Y. Ceramide biosynthesis in keratinocyte and its role in skin function. Biochimie. 2009;91:784-790.

  • [43] Mojumdar EH, Gooris GS, Barlow DJ, Lawrence MJ, Deme B, Bouwstra JA. Skin lipids: localization of ceramide and fatty acid in the unit cell of the long periodicity phase. Biophys J. 2015a;108:2670-2679.

  • [44] Mojumdar EH, Gooris GS, Bouwstra J. Phase behavior of skin lipid mixtures: the effect of cholesterol on lipid organization. Soft matter. 2015b;11:4326-4336.

  • [45] Mojumdar EH, Kariman Z, van Kerckhove L, Gooris GS, Bouwstra JA. The role of ceramide chain length distribution on the barrier properties of the skin lipid membranes. Biochim Biophys Acta. 2014;1838:2473-2483.

  • [46] Mori K, Matsuda H. Syntheisi of sphingosine relatives .10. Synthesis of (2S,3R,4E)-1-O-(beta-D-glucopyranosyl)-N- 30’- (linoleoyloxy)triacontanoyl-4-icosasphingenine, a new esterified cerebroside isolated from human and pig epidermis. Liebigs Ann. Chem. 1991:529-535.

  • [47] Motta S, Monti M, Sesana S, Caputo R, Carelli S, Ghidoni R. Ceramide composition of the psoriatic scale. Biochim Biophys Acta. 1993;1182:147-151.

  • [48] Muller S, Schmidt RR. Synthesis of two unique compounds, a ceramide and a cerebroside, occurring in human stratum corneum. J. Prakt. Chem. 2000;342:779-784.

  • [49] Neto DD, Gooris G, Bouwstra J. Effect of the omega-acylceramides on the lipid organization of stratum corneum model membranes evaluated by X-ray diffraction and FTIR studies (Part I). Chem. Phys. Lipids. 2011;164:184-195.

  • [50] Norlen L. Current understanding of skin barrier morphology. Skin Pharmacol Physiol. 2013;26:213-216.

  • [51] Norlen L, Nicander I, Lundsjo A, Cronholm T, Forslind B. A new HPLC-based method for the quantitative analysis of inner stratum corneum lipids with special reference to the free fatty acid fraction. Arch. Dermatol. Res. 1998;290:508-516.

  • [52] Novotny J, Hrabalek A, Vavrova K. Synthesis and structure-activity relationships of skin ceramides. Curr Med Chem. 2010;17:2301-2324.

  • [53] Novotny J, Janůšova B, Novotny M, Hrabalek A, Vavrova K. Short- -chain ceramides decrease skin barrier properties. Skin Pharmacol. Physiol. 2009;22:22-30.

  • [54] Opalka L, Kovačik A, Maixner J, Vavrova K. Omega-O-Acylceramides in Skin Lipid Membranes: Effects of Concentration, Sphingoid Base, and Model Complexity on Microstructure and Permeability. Langmuir. 2016;32:12894-12904.

  • [55] Opálka L, Kováčik A, Sochorová M, et al. Scalable Synthesis of Human Ultralong Chain Ceramides. Org. Lett. 2015;17:5456-5459.

  • [56] Pullmannova P, Staňkova K, Pospišilova M, Školova B, Zbytovska J, Vavrova K. Effects of sphingomyelin/ceramide ratio on the permeability and microstructure of model stratum corneum lipid membranes. BBA-Biomembranes. 2014;1838:2115-2126.

  • [57] Rabionet M, Bayerle A, Marsching C, et al. 1-O-acylceramides are natural components of human and mouse epidermis. J. Lipid. Res. 2013;54:3312-3321.

  • [58] Rabionet M, Gorgas K, Sandhoff R. Ceramide synthesis in the epidermis. Biochim Biophys Acta. 2014;1841:422-434.

  • [59] Rerek ME, Chen H, Markovic B, et al. Phytosphingosine and Sphingosine Ceramide Headgroup Hydrogen Bonding: Structural Insights through Thermotropic Hydrogen/Deuterium Exchange. J. Phys. Chem. B. 2001;105:9355 -9362.

  • [60] Robson KJ, Stewart ME, Michelsen S, Lazo ND, Downing DT. 6-Hydroxy-4-sphingenine in human epidermal ceramides. J. Lipid. Res. 1994;35:2060-2068.

  • [61] Shieh H-S, Hoard LG, Nordman CE. The structure of cholesterol. Acta Crystallogr Sect B. 1981;37:1538-1543.

  • [62] Schreiner V, Pfeiffer S, Lanzendorfer G, et al. Barrier characteristics of different human skin types investigated with X-ray diffraction, lipid analysis, and electron microscopy imaging. J. Invest. Dermatol. 2000;114:654-660.

  • [63] Skolova B, Hudska K, Pullmannova P, et al. Different phase behavior and packing of ceramides with long (C16) and very long (C24) acyls in model membranes: infrared spectroscopy using deuterated lipids. J Phys Chem B. 2014;118:10460-10470.

  • [64] Skolova B, Janusova B, Vavrova K. Ceramides with a pentadecasphingosine chain and short acyls have strong permeabilization effects on skin and model lipid membranes. Biochim Biophys Acta. 2016;1858:220-232.

  • [65] Skolova B, Janusova B, Zbytovska J, et al. Ceramides in the skin lipid membranes: length matters. Langmuir. 2013;29:15624-15633.

  • [66] Stahlberg S, Lange S, Dobner B, Huster D. Probing the Role of Ceramide Headgroup Polarity in Short-Chain Model Skin Barrier Lipid Mixtures by (2)H Solid-State NMR Spectroscopy. Langmuir. 2016;32:2023-2031.

  • [67] Stahlberg S, Skolova B, Madhu PK, Vogel A, Vavrova K, Huster D. Probing the role of the ceramide acyl chain length and sphingosine unsaturation in model skin barrier lipid mixtures by (2)H solid-state NMR spectroscopy. Langmuir. 2015;31:4906-4915.

  • [68] Školová B, Hudská Kr, Pullmannová P, et al. Different phase behavior and packing of ceramides with long (C16) and very long (C24) acyls in model membranes: infrared spectroscopy using deuterated lipids. J. Phys. Chem. B. 2014;118:10460-10470.

  • [69] Školova B, Janůšova B, Vavrova K. Ceramides with a pentadecasphingosine chain and short acyls have strong permeabilization effects on skin and model lipid membranes. BBA-Biomembranes. 2016;1858:220-232.

  • [70] Školová B, Janůšová B, Zbytovská J, et al. Ceramides in the skinlipid membranes: length matters. Langmuir. 2013;29:15624-15633.

  • [71] t’Kindt R, Jorge L, Dumont E, et al. Profiling and characterizing skin ceramides using reversed-phase liquid chromatography- -quadrupole time-of-flight mass spectrometry. Anal Chem. 2012;84:403-411.

  • [72] Uchida Y, Holleran WM. Omega-O-acylceramide, a lipid essential for mammalian survival. Journal of Dermatological Science. 2008;51:77-87.

  • [73] van Smeden J, Boiten WA, Hankemeier T, Rissmann R, Bouwstra JA, Vreeken RJ. Combined LC/MS-platform for analysis of all major stratum corneum lipids, and the profiling of skin substitutes. Biochim Biophys Acta. 2014a;1841:70-79.

  • [74] van Smeden J, Hoppel L, van der Heijden R, Hankemeier T, Vreeken RJ, Bouwstra JA. LC/MS analysis of stratum corneum lipids: ceramide profiling and discovery. J. Lipid Res. 2011;52:1211-1221.

  • [75] van Smeden J, Janssens M, Gooris GS, Bouwstra JA. The important role of stratum corneum lipids for the cutaneous barrier function. Biochim Biophys Acta. 2014b;1841:295-313.

  • [76] Vasireddy V, Uchida Y, Salem N, et al. Hum. Mol. Genet. 2007;16:471.

  • [77] Vavrova K, Henkes D, Struver K, et al. Filaggrin Deficiency Leads to Impaired Lipid Profile and Altered Acidification Pathways in a 3D Skin Construct. J Invest Dermatol. 2014;134:746-753.

  • [78] Wertz PW, Madison KC, Downing DT. Covalently bound lipids of human stratum corneum. J. Invest. Dermatol. 1989;92:109-111.

  • [79] White SH, Mirejovsky D, King GI. Structure of lamellar lipid domains and corneocyte envelopes of murine stratum corneum. An X-ray diffraction study. Biochemistry. 1988;27:3725-3732.

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