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Sphingolipids and Inflammatory Diseases of the Skin

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Sphingolipids in Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 216))

Abstract

Mammalian skin protects our body against external assaults due to a well-organized skin barrier. The formation of the skin barrier is a complex process, in which basal keratinocytes lose their mitotic activity and differentiate to corneocytes. These corneocytes are embedded in intercellular lipid lamellae composed of ceramides, cholesterol, fatty acids, and cholesterol esters. Ceramides are the dominant lipid molecules and their reduction is connected with a transepidermal water loss and an epidermal barrier dysfunction resulting in inflammatory skin diseases. Moreover, bioactive sphingolipid metabolites like ceramide-1-phosphate, sphingosylphosphorylcholine, and sphingosine-1-phosphate are also involved in the biological modulation of keratinocytes and immune cells of the skin. Therefore, it is not astonishing that a dysregulation of sphingolipid metabolism has been identified in inflammatory skin diseases such as atopic dermatitis and psoriasis vulgaris. This chapter will describe not only the specific sphingolipid species and their skin functions but also the dysregulation of sphingolipid metabolism in inflammatory skin diseases.

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References

  • Aho S, Harding CR, Lee JM, Meldrum H, Bosko CA (2012) Regulatory role for the profilaggrin N-terminal domain in epidermal homeostasis. J Invest Dermatol 132(10):2376–2385

    Article  PubMed  CAS  Google Scholar 

  • Alessandrini F, Stachowitz S, Ring J, Behrendt H (2001) The level of prosaposin is decreased in the skin of patients with psoriasis vulgaris. J Invest Dermatol 116:394–400

    Article  PubMed  CAS  Google Scholar 

  • Andoh T, Haza S, Saito A, Kuraishi Y (2011) Involvement of leukotriene B4 in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Exp Dermatol 20:894–898

    Article  PubMed  CAS  Google Scholar 

  • Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G (2002) Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 119:433–439

    Article  PubMed  CAS  Google Scholar 

  • Baumer W, Rossbach K, Mischke R, Reines I, Langbein-Detsch I, Luth A, Kleuser B (2011) Decreased concentration and enhanced metabolism of sphingosine-1-phosphate in lesional skin of dogs with atopic dermatitis: disturbed sphingosine-1-phosphate homeostasis in atopic dermatitis. J Invest Dermatol 131:266–268

    Article  PubMed  Google Scholar 

  • Behne M, Uchida Y, Seki T, de Montellano PO, Elias PM, Holleran WM (2000) Omega-hydroxyceramides are required for corneocyte lipid envelope (CLE) formation and normal epidermal permeability barrier function. J Invest Dermatol 114:185–192

    Article  PubMed  CAS  Google Scholar 

  • Bektas M, Dullin Y, Wieder T, Kolter T, Sandhoff K, Brossmer R, Ihrig P, Orfanos CE, Geilen CC (1998) Induction of apoptosis by synthetic ceramide analogues in the human keratinocyte cell line HaCaT. Exp Dermatol 7:342–349

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD (2012) Vitamin D and the skin: physiology and pathophysiology. Rev Endocr Metab Disord 13:3–19

    Article  PubMed  CAS  Google Scholar 

  • Bornancin F (2011) Ceramide kinase: the first decade. Cell Signal 23:999–1008

    Article  PubMed  CAS  Google Scholar 

  • Choi H, Kim S, Kim HJ, Kim KM, Lee CH, Shin JH, Noh M (2010) Sphingosylphosphorylcholine down-regulates filaggrin gene transcription through NOX5-based NADPH oxidase and cyclooxygenase-2 in human keratinocytes. Biochem Pharmacol 80:95–103

    Article  PubMed  CAS  Google Scholar 

  • Christensen AD, Haase C (2012) Immunological mechanisms of contact hypersensitivity in mice. APMIS 120:1–27

    Article  PubMed  CAS  Google Scholar 

  • De Benedetto A, Kubo A, Beck LA (2012) Skin barrier disruption: a requirement for allergen sensitization? J Invest Dermatol 132:949–963

    Article  PubMed  Google Scholar 

  • Deigner HP, Claus R, Bonaterra GA, Gehrke C, Bibak N, Blaess M, Cantz M, Metz J, Kinscherf R (2001) Ceramide induces aSMase expression: implications for oxLDL-induced apoptosis. FASEB J 15:807–814

    Article  PubMed  CAS  Google Scholar 

  • Di Cesare A, Di Meglio P, Nestle FO (2009) The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 129:1339–1350

    Article  PubMed  Google Scholar 

  • Doering T, Holleran WM, Potratz A, Vielhaber G, Elias PM, Suzuki K, Sandhoff K (1999) Sphingolipid activator proteins are required for epidermal permeability barrier formation. J Biol Chem 274:11038–11045

    Article  PubMed  CAS  Google Scholar 

  • Geilen CC, Bektas M, Wieder T, Orfanos CE (1996) The vitamin D3 analogue, calcipotriol, induces sphingomyelin hydrolysis in human keratinocytes. FEBS Lett 378:88–92

    Article  PubMed  CAS  Google Scholar 

  • Geilen CC, Bektas M, Wieder T, Kodelja V, Goerdt S, Orfanos CE (1997) 1alpha,25-dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor alpha. J Biol Chem 272:8997–9001

    Article  PubMed  CAS  Google Scholar 

  • Hamanaka S, Hara M, Nishio H, Otsuka F, Suzuki A, Uchida Y (2002) Human epidermal glucosylceramides are major precursors of stratum corneum ceramides. J Invest Dermatol 119:416–423

    Article  PubMed  CAS  Google Scholar 

  • Hansen HS, Jensen B (1985) Essential function of linoleic acid esterified in acylglucosylceramide and acylceramide in maintaining the epidermal water permeability barrier. Evidence from feeding studies with oleate, linoleate, arachidonate, columbinate and alpha-linolenate. Biochim Biophys Acta 834:357–363

    Article  PubMed  CAS  Google Scholar 

  • Higuchi K, Hara J, Okamoto R, Kawashima M, Imokawa G (2000) The skin of atopic dermatitis patients contains a novel enzyme, glucosylceramide sphingomyelin deacylase, which cleaves the N-acyl linkage of sphingomyelin and glucosylceramide. Biochem J 350(Pt 3):747–756

    Article  PubMed  CAS  Google Scholar 

  • Higuchi K, Kawashima M, Takagi Y, Kondo H, Yada Y, Ichikawa Y, Imokawa G (2001) Sphingosylphosphorylcholine is an activator of transglutaminase activity in human keratinocytes. J Lipid Res 42:1562–1570

    PubMed  CAS  Google Scholar 

  • Holleran WM, Ginns EI, Menon GK, Grundmann JU, Fartasch M, McKinney CE, Elias PM, Sidransky E (1994) Consequences of beta-glucocerebrosidase deficiency in epidermis. Ultrastructure and permeability barrier alterations in Gaucher disease. J Clin Invest 93:1756–1764

    Article  PubMed  CAS  Google Scholar 

  • Holleran WM, Takagi Y, Uchida Y (2006) Epidermal sphingolipids: metabolism, function, and roles in skin disorders. FEBS Lett 580:5456–5466

    Article  PubMed  CAS  Google Scholar 

  • Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A (1991) Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 96:523–526

    Article  PubMed  CAS  Google Scholar 

  • Imokawa G, Takagi Y, Higuchi K, Kondo H, Yada Y (1999) Sphingosylphosphorylcholine is a potent inducer of intercellular adhesion molecule-1 expression in human keratinocytes. J Invest Dermatol 112:91–96

    Article  PubMed  CAS  Google Scholar 

  • Ishibashi M, Arikawa J, Okamoto R, Kawashima M, Takagi Y, Ohguchi K, Imokawa G (2003) Abnormal expression of the novel epidermal enzyme, glucosylceramide deacylase, and the accumulation of its enzymatic reaction product, glucosylsphingosine, in the skin of patients with atopic dermatitis. Lab Invest 83:397–408

    PubMed  CAS  Google Scholar 

  • Jennemann R et al (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet 21:586–608

    Article  PubMed  CAS  Google Scholar 

  • Jensen JM, Proksch E (2009) The skin’s barrier. G Ital Dermatol Venereol 144:689–700

    PubMed  CAS  Google Scholar 

  • Jensen JM, Folster-Holst R, Baranowsky A, Schunck M, Winoto-Morbach S, Neumann C, Schutze S, Proksch E (2004) Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J Invest Dermatol 122:1423–1431

    Article  PubMed  CAS  Google Scholar 

  • Jiang YJ, Uchida Y, Lu B, Kim P, Mao C, Akiyama M, Elias PM, Holleran WM, Grunfeld C, Feingold KR (2009) Ceramide stimulates ABCA12 expression via peroxisome proliferator-activated receptor delta in human keratinocytes. J Biol Chem 284:18942–18952

    Article  PubMed  CAS  Google Scholar 

  • Jin K, Higaki Y, Takagi Y, Higuchi K, Yada Y, Kawashima M, Imokawa G (1994) Analysis of beta-glucocerebrosidase and ceramidase activities in atopic and aged dry skin. Acta Derm Venereol 74:337–340

    PubMed  CAS  Google Scholar 

  • Jung EM, Griner RD, Mann-Blakeney R, Bollag WB (1998) A potential role for ceramide in the regulation of mouse epidermal keratinocyte proliferation and differentiation. J Invest Dermatol 110:318–323

    Article  PubMed  CAS  Google Scholar 

  • Kaplan DH (2010) In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol 31:446–451

    Article  PubMed  CAS  Google Scholar 

  • Kim HJ, Kim H, Han ES, Park SM, Koh JY, Kim KM, Noh MS, Kim JJ, Lee CH (2008) Characterizations of sphingosylphosphorylcholine-induced scratching responses in ICR mice using naltrexon, capsaicin, ketotifen and Y-27632. Eur J Pharmacol 583:92–96

    Article  PubMed  CAS  Google Scholar 

  • Kubo A, Nagao K, Amagai M (2012) Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest 122:440–447

    Article  PubMed  CAS  Google Scholar 

  • Lampe MA, Williams ML, Elias PM (1983) Human epidermal lipids: characterization and modulations during differentiation. J Lipid Res 24:131–140

    PubMed  CAS  Google Scholar 

  • Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665–1674

    Article  PubMed  CAS  Google Scholar 

  • Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 366:1190–1199

    Article  PubMed  CAS  Google Scholar 

  • Lichte K, Rossi R, Danneberg K, ter Braak M, Kurschner U, Jakobs KH, Kleuser B, Meyer zu Heringdorf D (2008) Lysophospholipid receptor-mediated calcium signaling in human keratinocytes. J Invest Dermatol 128:1487–1498

    Article  PubMed  CAS  Google Scholar 

  • Liu YY et al (2008) A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J 22:2541–2551

    Article  PubMed  CAS  Google Scholar 

  • Lowes MA, Bowcock AM, Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445:866–873

    Article  PubMed  CAS  Google Scholar 

  • Maceyka M, Harikumar KB, Milstien S, Spiegel S (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22:50–60

    Article  PubMed  CAS  Google Scholar 

  • Macheleidt O, Kaiser HW, Sandhoff K (2002) Deficiency of epidermal protein-bound omega-hydroxyceramides in atopic dermatitis. J Invest Dermatol 119:166–173

    Article  PubMed  CAS  Google Scholar 

  • Manggau M, Kim DS, Ruwisch L, Vogler R, Korting HC, Schafer-Korting M, Kleuser B (2001) 1Alpha,25-dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate. J Invest Dermatol 117:1241–1249

    Article  PubMed  CAS  Google Scholar 

  • Marsella R, Girolomoni G (2009) Canine models of atopic dermatitis: a useful tool with untapped potential. J Invest Dermatol 129:2351–2357

    Article  PubMed  CAS  Google Scholar 

  • Masukawa Y et al (2008) Characterization of overall ceramide species in human stratum corneum. J Lipid Res 49:1466–1476

    Article  PubMed  CAS  Google Scholar 

  • Mechtcheriakova D et al (2007) Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses. Cell Signal 19:748–760

    Article  PubMed  CAS  Google Scholar 

  • Menon GK, Grayson S, Elias PM (1986) Cytochemical and biochemical localization of lipase and sphingomyelinase activity in mammalian epidermis. J Invest Dermatol 86:591–597

    Article  PubMed  CAS  Google Scholar 

  • Meyer T, Stockfleth E, Christophers E (2007) Immune response profiles in human skin. Br J Dermatol 157(Suppl 2):1–7

    Article  PubMed  CAS  Google Scholar 

  • Mizutani Y, Kihara A, Igarashi Y (2006) LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem J 398:531–538

    Article  PubMed  CAS  Google Scholar 

  • Mizutani Y, Kihara A, Chiba H, Tojo H, Igarashi Y (2008) 2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length. J Lipid Res 49:2356–2364

    Article  PubMed  CAS  Google Scholar 

  • Motta S, Monti M, Sesana S, Caputo R, Carelli S, Ghidoni R (1993) Ceramide composition of the psoriatic scale. Biochim Biophys Acta 1182:147–151

    Article  PubMed  CAS  Google Scholar 

  • Motta S, Sesana S, Monti M, Giuliani A, Caputo R (1994a) Interlamellar lipid differences between normal and psoriatic stratum corneum. Acta Derm Venereol Suppl (Stockh) 186:131–132

    CAS  Google Scholar 

  • Motta S, Monti M, Sesana S, Mellesi L, Ghidoni R, Caputo R (1994b) Abnormality of water barrier function in psoriasis. Role of ceramide fractions. Arch Dermatol 130:452–456

    Article  PubMed  CAS  Google Scholar 

  • Motta S, Sesana S, Ghidoni R, Monti M (1995) Content of the different lipid classes in psoriatic scale. Arch Dermatol Res 287:691–694

    Article  PubMed  CAS  Google Scholar 

  • Nickoloff BJ, Qin JZ, Nestle FO (2007) Immunopathogenesis of psoriasis. Clin Rev Allergy Immunol 33:45–56

    Article  PubMed  CAS  Google Scholar 

  • Ohnishi Y, Okino N, Ito M, Imayama S (1999) Ceramidase activity in bacterial skin flora as a possible cause of ceramide deficiency in atopic dermatitis. Clin Diagn Lab Immunol 6:101–104

    PubMed  CAS  Google Scholar 

  • Okazaki T, Bell RM, Hannun YA (1989) Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J Biol Chem 264:19076–19080

    PubMed  CAS  Google Scholar 

  • Quazi F, Molday RS (2011) Lipid transport by mammalian ABC proteins. Essays Biochem 50:265–290

    Article  PubMed  CAS  Google Scholar 

  • Radeke HH, von Wenckstern H, Stoidtner K, Sauer B, Hammer S, Kleuser B (2005) Overlapping signaling pathways of sphingosine 1-phosphate and TGF-beta in the murine Langerhans cell line XS52. J Immunol 174:2778–2786

    PubMed  CAS  Google Scholar 

  • Rajpopat S et al (2011) Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol 147:681–686

    Article  PubMed  Google Scholar 

  • Reines I, Kietzmann M, Mischke R, Tschernig T, Luth A, Kleuser B, Baumer W (2009) Topical application of sphingosine-1-phosphate and FTY720 attenuate allergic contact dermatitis reaction through inhibition of dendritic cell migration. J Invest Dermatol 129:1954–1962

    Article  PubMed  CAS  Google Scholar 

  • Rose L, Schneider C, Stock C, Zollner TM, Docke WD (2012) Extended DNFB-induced contact hypersensitivity models display characteristics of chronic inflammatory dermatoses. Exp Dermatol 21:25–31

    Article  PubMed  CAS  Google Scholar 

  • Sallusto F, Nicolo C, De Maria R, Corinti S, Testi R (1996) Ceramide inhibits antigen uptake and presentation by dendritic cells. J Exp Med 184:2411–2416

    Article  PubMed  CAS  Google Scholar 

  • Santinha DR, Marques DR, Maciel EA, Simoes CS, Rosa S, Neves BM, Macedo B, Domingues P, Cruz MT, Domingues MR (2012) Profiling changes triggered during maturation of dendritic cells: a lipidomic approach. Anal Bioanal Chem 403:457–471

    Article  PubMed  CAS  Google Scholar 

  • Sauer B, Vogler R, von Wenckstern H, Fujii M, Anzano MB, Glick AB, Schafer-Korting M, Roberts AB, Kleuser B (2004) Involvement of Smad signaling in sphingosine 1-phosphate-mediated biological responses of keratinocytes. J Biol Chem 279:38471–38479

    Article  PubMed  CAS  Google Scholar 

  • Schroder M, Richter C, Juan MH, Maltusch K, Giegold O, Quintini G, Pfeilschifter JM, Huwiler A, Radeke HH (2011) The sphingosine kinase 1 and S1P1 axis specifically counteracts LPS-induced IL-12p70 production in immune cells of the spleen. Mol Immunol 48:1139–1148

    Article  PubMed  Google Scholar 

  • Schulze T, Golfier S, Tabeling C, Rabel K, Graler MH, Witzenrath M, Lipp M (2011) Sphingosine-1-phospate receptor 4 (S1P(4)) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model. FASEB J 25:4024–4036

    Article  PubMed  CAS  Google Scholar 

  • Schuppel M, Kurschner U, Kleuser U, Schafer-Korting M, Kleuser B (2008) Sphingosine 1-phosphate restrains insulin-mediated keratinocyte proliferation via inhibition of Akt through the S1P2 receptor subtype. J Invest Dermatol 128:1747–1756

    Article  PubMed  Google Scholar 

  • Seo EY, Park GT, Lee KM, Kim JA, Lee JH, Yang JM (2006) Identification of the target genes of atopic dermatitis by real-time PCR. J Invest Dermatol 126:1187–1189

    Article  PubMed  CAS  Google Scholar 

  • Steinman RM (2007) Dendritic cells: understanding immunogenicity. Eur J Immunol 37(Suppl 1):S53–S60

    Article  PubMed  CAS  Google Scholar 

  • Tamargo RJ, Velayati A, Goldin E, Sidransky E (2012) The role of saposin C in Gaucher disease. Mol Genet Metab 106:257–263

    Article  PubMed  CAS  Google Scholar 

  • Tsuji K, Mitsutake S, Yokose U, Sugiura M, Kohama T, Igarashi Y (2008) Role of ceramide kinase in peroxisome proliferator-activated receptor beta-induced cell survival of mouse keratinocytes. FEBS J 275:3815–3826

    Article  PubMed  CAS  Google Scholar 

  • Uchida Y, Holleran WM (2008) Omega-O-acylceramide, a lipid essential for mammalian survival. J Dermatol Sci 51:77–87

    Article  PubMed  CAS  Google Scholar 

  • Uchida Y, Hara M, Nishio H, Sidransky E, Inoue S, Otsuka F, Suzuki A, Elias PM, Holleran WM, Hamanaka S (2000) Epidermal sphingomyelins are precursors for selected stratum corneum ceramides. J Lipid Res 41:2071–2082

    PubMed  CAS  Google Scholar 

  • Vogler R, Sauer B, Kim DS, Schafer-Korting M, Kleuser B (2003) Sphingosine-1-phosphate and its potentially paradoxical effects on critical parameters of cutaneous wound healing. J Invest Dermatol 120:693–700

    Article  PubMed  CAS  Google Scholar 

  • Wakita H, Tokura Y, Yagi H, Nishimura K, Furukawa F, Takigawa M (1994) Keratinocyte differentiation is induced by cell-permeant ceramides and its proliferation is promoted by sphingosine. Arch Dermatol Res 286:350–354

    Article  PubMed  CAS  Google Scholar 

  • Wakita H, Matsushita K, Nishimura K, Tokura Y, Furukawa F, Takigawa M (1998) Sphingosylphosphorylcholine stimulates proliferation and upregulates cell surface-associated plasminogen activator activity in cultured human keratinocytes. J Invest Dermatol 110:253–258

    Article  PubMed  CAS  Google Scholar 

  • Wood SH, Clements DN, Ollier WE, Nuttall T, McEwan NA, Carter SD (2009) Gene expression in canine atopic dermatitis and correlation with clinical severity scores. J Dermatol Sci 55:27–33

    Article  PubMed  CAS  Google Scholar 

  • Zuo Y, Zhuang DZ, Han R, Isaac G, Tobin JJ, McKee M, Welti R, Brissette JL, Fitzgerald ML, Freeman MW (2008) ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol Chem 283:36624–36635

    Article  PubMed  CAS  Google Scholar 

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Kleuser, B., Japtok, L. (2013). Sphingolipids and Inflammatory Diseases of the Skin. In: Gulbins, E., Petrache, I. (eds) Sphingolipids in Disease. Handbook of Experimental Pharmacology, vol 216. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1511-4_18

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