Skip to main content

Skin barrier function

Abstract

Like other inflammatory dermatoses, the pathogenesis of atopic dermatitis (AD) has been largely attributed to abnormalities in adaptive immunity. T helper (Th) cell types 1 and 2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling are thought to account for the chronic, pruritic, and inflammatory dermatosis that characterizes AD. Not surprisingly, therapy has been directed toward ameliorating Th2-mediated inflammation and pruritus. Here, we review emerging evidence that inflammation in AD occurs downstream to inherited and acquired insults to the barrier. Therapy based upon this new view of pathogenesis should emphasize approaches that correct the primary abnormality in barrier function, which drives downstream inflammation and allows unrestricted antigen access.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

  1. 1.

    Elias PM: Stratum corneum defensive functions: an integrated view. J Invest Dermatol 2005, 125:183–200.

    PubMed  CAS  Google Scholar 

  2. 2.

    Elias PM, Menon GK: Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 1991, 24:1–26.

    PubMed  CAS  Google Scholar 

  3. 3.

    Brattsand M, Stefansson K, Lundh C, et al.: A proteolytic cascade of kallikreins in the stratum corneum. J Invest Dermatol 2005, 124:198–203.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Braff MH, Di Nardo A, Gallo RL: Keratinocytes store the antimicrobial peptide cathelicidin in lamellar bodies. J Invest Dermatol 2005, 124:394–400.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Oren A, Ganz T, Liu L, Meerloo T: In human epidermis, beta-defensin 2 is packaged in lamellar bodies. Exp Mol Pathol 2003, 74:180–182.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Aberg K, Radek K, Choi E, et al.: Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest 2007, 117:3339–3349.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Sugarman JL, Fluhr JW, Fowler AJ, et al.: The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease. Arch Dermatol 2003, 139:1417–1422.

    PubMed  Article  Google Scholar 

  8. 8.

    Seidenari S, Giusti G: Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin. Acta Derm Venereol 1995, 75:429–433.

    PubMed  CAS  Google Scholar 

  9. 9.

    Proksch E, Folster-Holst R, Jensen JM: Skin barrier function, epidermal proliferation and differentiation in eczema. J Dermatol Sci 2006, 43:159–169.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Chamlin SL, Kao J, Frieden IJ, et al.: Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002, 47:198–208.

    PubMed  Article  Google Scholar 

  11. 11.

    Leung DY, Soter NA: Cellular and immunologic mechanisms in atopic dermatitis. J Am Acad Dermatol 2001, 44:S1–S12.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Leung DY, Bieber T: Atopic dermatitis. Lancet 2003, 361:151–160.

    PubMed  Article  Google Scholar 

  13. 13.

    Leung DY, Boguniewicz M, Howell MD, et al.: New insights into atopic dermatitis. J Clin Invest 2004, 113:651–657.

    PubMed  CAS  Google Scholar 

  14. 14.

    Elias PM, Wood LC, Feingold KR: Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermat 1999, 10:119–126.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Elias PM, Feingold KR: Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol 2001, 137:1079–1081.

    PubMed  CAS  Google Scholar 

  16. 16.

    Taieb A: Hypothesis: from epidermal barrier dysfunction to atopic disorders. Contact Dermatitis 1999, 41:177–180.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Eberlein-Konig B, Schafer T, Huss-Marp J, et al.: Skin surface pH, stratum corneum hydration, trans-epidermal water loss and skin roughness related to atopic eczema and skin dryness in a population of primary school children. Acta Derm Venereol 2000, 80:188–191.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Cork MJ, Britton J, Butler L, et al.: Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse. Br J Dermatol 2003, 149:582–589.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Elias PM: The skin barrier as an innate immune element. Sem Immunopath 2007, 29:3–14.

    Article  Google Scholar 

  20. 20.

    Aly R, Maibach HI, Shinefield HR: Microbial flora of atopic dermatitis. Arch Dermatol 1977, 113:780–782.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Baker BS: The role of microorganisms in atopic dermatitis. Clin Exp Immunol 2006, 144:1–9.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Aberg KM, Man MQ, Gallo RL, et al.: Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers. J Invest Dermatol 2008, 128:917–925.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Miller SJ, Aly R, Shinefeld HR, Elias PM: In vitro and in vivo antistaphylococcal activity of human stratum corneum lipids. Arch Dermatol 1988, 124:209–215.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Fluhr JW, Elias PM: Stratum corneum pH: Formation and function of the ‘acid mantle’. Exog Dermatol 2002, 1:163–175.

    Article  CAS  Google Scholar 

  25. 25.

    Bibel DJ, Aly R, Shinefield HR: Antimicrobial activity of sphingosines. J Invest Dermatol 1992, 98:269–273.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Clarke SR, Mohamed R, Bian L, et al.: The Staphylococcus aureus surface protein IsdA mediates resistance to innate defenses of human skin. Cell Host Microbe 2007, 1:199–212.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Ong PY, Ohtake T, Brandt C, et al.: Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002, 347:1151–1160.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Nomura I, Goleva E, Howell MD, et al.: Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 2003, 171:3262–3269.

    PubMed  CAS  Google Scholar 

  29. 29.

    Zaiou M, Nizet V, Gallo RL: Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol 2003, 120:810–816.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Komatsuzawa H, Ouhara K, Yamada S, et al.: Innate defences against methicillin-resistant Staphylococcus aureus (MRSA) infection. J Pathol 2006, 208:249–260.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Lomholt H, Andersen KE, Kilian M: Staphylococcus aureus clonal dynamics and virulence factors in children with atopic dermatitis. J Invest Dermatol 2005, 125:977–982.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Gould HJ, Takhar P, Harries HE, et al.: The allergic march from Staphylococcus aureus superantigens to immunoglobulin E. Chem Immunol Allergy 2007, 93:106–136.

    PubMed  Article  Google Scholar 

  33. 33.

    Sonkoly E, Muller A, Lauerma AI, et al.: IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 2006, 117:411–417.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Denda M, Sato J, Tsuchiya T, et al.: Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication for seasonal exacerbations of inflammatory dermatoses. J Invest Dermatol 1998, 111:873–878.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al.: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006, 38:441–446.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Weidinger S, Illig T, Baurecht H, et al.: Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006, 118:214–219.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Hudson TJ: Skin barrier function and allergic risk. Nat Genet 2006, 38:399–400.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Hachem JP, Crumrine D, Fluhr J, et al.: pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 2003, 121:345–353.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Sandilands A, Smith FJ, Irvine AD, McLean WH: Filaggrin’s fuller figure: a glimpse into the genetic architecture of atopic dermatitis. J Invest Dermatol 2007, 17:1282–1284.

    Article  Google Scholar 

  40. 40.

    Weidinger S, Rodriguez E, Stahl C, et al.: Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 2007, 127:724–726.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Scott IR, Harding CR: Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment. Dev Biol 1986, 115:84–92.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Krien P, Kermici M: Evidence for the existence of a self-regulated enzymatic process within human stratum corneum-an unexpected role for urocanic acid. J Invest Dermatol 2000, 115:414–420.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Walley AJ, Chavanas S, Moffatt MF, et al.: Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001, 29:175–178.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Hachem JP, Wagberg F, Schmuth M, et al.: Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Invest Dermatol 2006, 126:1609–1621.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Komatsu N, Takata M, Otsuki N, et al.: Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J Invest Dermatol 2002, 118:436–443.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Di Nardo A, Wertz P, Giannetti A, Seidenari S: Ceramide and cholesterol composition of the skin of patients with atopic dermatitis. Acta Derm Venereol 1998, 78:27–30.

    PubMed  Article  Google Scholar 

  47. 47.

    Imokawa G, Abe A, Jin K, et al.: Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 1991, 96:523–526.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Cork MJ, Robinson DA, Vasilopoulos Y, et al.: New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 2006, 118:3–21; quiz 22–23.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Garg A, Chren MM, Sands LP, et al.: Psychological stress perturbs epidermal permeability barrier homeostasis: implications for the pathogenesis of stress-associated skin disorders. Arch Dermatol 2001, 137:53–59.

    PubMed  CAS  Google Scholar 

  50. 50.

    Altemus M, Rao B, Dhabhar FS, et al.: Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol 2001, 117:309–317.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Kurahashi R, Hatano Y, Katagiri C: IL-4 suppresses the recovery of cutaneous permeability barrier functions in vivo. J Invest Dermatol 2008, in press.

  52. 52.

    Hatano Y, Terashi H, Arakawa S, Katagiri K: Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis. J Invest Dermatol 2005, 124:786–792.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Howell MD, Kim BE, Gao P, et al.: Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007, 120:150–155.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Kobayashi J, Inai T, Morita K, et al.: Reciprocal regulation of permeability through a cultured keratinocyte sheet by IFN-gamma and IL-4. Cytokine 2004, 28:186–189.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Elias PM, Hatano Y, Williams ML: Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol 2008, 2008 Mar 6 (Epub ahead of print).

  56. 56.

    Sugarman J, Parish LJ: A topical lipid-based barrier repair formulation (EpiCeramTM cream) is high-effective monotherapy for moderate-to-severe pediatric atopic dermatitis. J Invest Dermatol 2008, in press.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Peter M. Elias.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Elias, P.M. Skin barrier function. Curr Allergy Asthma Rep 8, 299–305 (2008). https://doi.org/10.1007/s11882-008-0048-0

Download citation

Keywords

  • Atopic Dermatitis
  • Dermatol
  • Stratum Corneum
  • Allergy Clin Immunol
  • Permeability Barrier