Skip to main content

Advertisement

SpringerLink
Log in

Keratinocytes in Atopic dermatitis: Inflammatory signals

  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that usually predates the development of allergic airway disease. In most cases, this is thought to be an allergen-driven disease with prominent roles played by antigen presenting cells and effector Th2 cells. But keratinocytes, by virtue of their location, provide an important window to the environment and are also thought to contribute to the development of AD. In this review, we discuss several biologic attributes of keratinocytes that are relevant for AD: 1) intrinsic defects in barrier function, 2) production of inflammatory mediators that promote or maintain allergic inflammation, 3) keratinocyte apoptosis, 4) effects of staphylococcal toxins on keratinocytes, and 5) potential consequences of the expression of cosignaling molecules (eg, B7 family members) and receptors important for innate immune responses (eg, Toll receptors). Clearly, these findings have highlighted a more active role played by the epithelium than was previously recognized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Hanifin JM, Rajka G: Diagnostic criteria for atopic dermatitis. Acta Derm Venereol 1980, 93:44–47.

    Google Scholar 

  2. Williams HC, Burney PG, Hay RJ, et al.: The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 1994, 131:383–396.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Novak N, Bieber T: Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol 2003, 112:252–262.

    Article  PubMed  Google Scholar 

  5. Werner Y, Lindberg M: Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol 1985, 65:102–105.

    PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. Wood LC, Jackson SM, Elias PM, et al.: Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J Clin Invest 1992, 90:482–487.

    PubMed  CAS  Google Scholar 

  8. Yamamoto A, Serizawa S, Ito M, et al.: Stratum corneum lipid abnormalities in atopic dermatitis. Arch Dermatol Res 1991, 283:219–223.

    Article  PubMed  CAS  Google Scholar 

  9. Hara J, Higuchi K, Okamoto R, et al.: High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis. J Invest Dermatol 2000, 115:406–413. Sphingomyelin deacylase is highly expressed in the epidermis of AD patients, and competes with sphingomyelinase or beta-glucocerebrosidase for the common substrate sphingomyelin or glucosylceramide, which leads to the ceramide deficiency of the stratum corneum in AD.

    Article  PubMed  CAS  Google Scholar 

  10. Wakita H, Matsushita K, Nishimura K, et al.: Sphingosylphosphorylcholine stimulates proliferation and upregulates cellsurface -associated plasminogen activator activity in cultured human keratinocytes. J Invest Dermatol 1998, 110:253–258.

    Article  PubMed  CAS  Google Scholar 

  11. Arikawa J, Ishibashi M, Kawashima M, et al.: 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 2002, 119:433–439.

    Article  PubMed  CAS  Google Scholar 

  12. Soumelis V, Reche PA, Kanzler H, et al.: Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002, 3:673–680. Thymic stromal lymphopoietin (TSLP) initiates allergic inflammation by activating CD11c+ DCs and inducing the Th2-attracting chemokines TARC (CCL17) and MDC (CCL22). TSLP-activated DCs prime naïve Th cells to produce the proallergic cytokines IL-4, IL-5, IL-13, and TNF-à, and downregulate IL-10 and IFN-γ.

    Article  PubMed  CAS  Google Scholar 

  13. Pastore S, Fanales-Belasio E, Albanesi C, et al.: Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis: implications for sustained dendritic cell activation in the skin. J Clin Invest 1997, 99:3009–3017. Enhanced production of GM-CSF by epidermal keratinocytes appears to contribute to promotion and maintenance of AD lesions, in particular to the increased number, sustained activation, and enhanced antigen-presenting functions of DCs.

    PubMed  CAS  Google Scholar 

  14. Pastore S, Giustizieri ML, Mascia F, et al.: Dysregulated activation of activator protein 1 in keratinocytes of atopic dermatitis patients with enhanced expression of granulocyte/ macrophage-colony stimulating factor. J Invest Dermatol 2000, 115:1134–1143.

    Article  PubMed  CAS  Google Scholar 

  15. Beck LA, Leung DYM: Allergen sensitization through the skin induces systemic allergic responses. J Allergy Clin Immunol 2000, 106:S258-S263.

    Article  PubMed  CAS  Google Scholar 

  16. Vestergaard C, Band K, Gesser B, et al.: A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin. J Invest Dermatol 2000, 115:640–646.

    Article  PubMed  CAS  Google Scholar 

  17. Homey B, Alenius H, Muller A, et al.: CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med 2002, 8:157–165. The interaction of CCL27 with CCR10 mediates the skin-specific homing of pathogenic T cells that participate in skin inflammation in diseases, such as psoriasis or atopic dermatitis.

    Article  PubMed  CAS  Google Scholar 

  18. Giustizieri ML, Mascia F, Frezzolini A, et al.: Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines. J Allergy Clin Immunol 2001, 107:871–877.

    Article  PubMed  CAS  Google Scholar 

  19. Taha RA, Minshall EM, Leung DY, et al.: Evidence for increased expression of eotaxin and monocyte chemotactic protein-4 in atopic dermatitis. J Allergy Clin Immunol 2000, 105:1002–1007.

    Article  PubMed  CAS  Google Scholar 

  20. Klunker S, Trautmann A, Akdis M, et al.: A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IP-10, Mig and ITAC for T cell chemotaxis towards epidermis in atopic dermatitis. J Immunol 2003, 171:1078–1084.

    PubMed  CAS  Google Scholar 

  21. Uchi H, Terao H, Koga T, et al.: Cytokines and chemokines in the epidermis. J Dermatol Sci 2000, 24(Suppl 1):S29-S38.

    Article  PubMed  CAS  Google Scholar 

  22. Trautmann A, Akdis M, Kleeman D, et al.: T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000, 106:25–35. T-cell-mediated keratinocyte apoptosis contributes to AD formation. Induction of apoptosis requires IFN-γ, which induces expression of Fas on keratinocytes.

    Article  PubMed  CAS  Google Scholar 

  23. Trautmann A, Akdis M, Schmid-Grendelmeier P, et al.:Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis. J Allergy Clin Immunol 2001, 108:839–846.

    Article  PubMed  CAS  Google Scholar 

  24. Travers JB, Norris DA, Leung DY: The keratinocyte as a target for staphylococcal bacterial toxins. J Investig Dermatol Symp Proc 2001, 6:225–230.

    Article  PubMed  CAS  Google Scholar 

  25. Cho SH, Strickland I, Tomkinson A, et al.: Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model. J Invest Dermatol 2001, 116:658–663.

    Article  PubMed  CAS  Google Scholar 

  26. 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. A deficiency in the expression of antimicrobial peptides might account for the susceptibility of patients with atopic dermatitis to skin infection with S. aureus.

    Article  PubMed  CAS  Google Scholar 

  27. 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 

  28. Steinman RM: Some interfaces of dendritic cell biology. APMIS 2003, 111:675–697.

    Article  PubMed  CAS  Google Scholar 

  29. Rietz C, Chen L: New B7 family members with positive and negative costimulatory function. Am J Transplant 2004, 4:8–14. This review focuses on new costimulatory pathways belonging to the B7 family. The authors discuss T-cell regulation, contributing to the understanding of the intricate control of T-cell immunity. Possibilities for manipulating these costimulatory pathways for a new therapeutic fine-tuning of the immune system are proposed.

    Article  PubMed  CAS  Google Scholar 

  30. Petroff MG, Chen L, Phillips TA, et al.: B7 family molecules: novel immunomodulators at the maternal-fetal interface. Placenta 2002, 23(Suppl A):S95-S101.

    Article  PubMed  Google Scholar 

  31. Williams IR, Kupper TS: Immunity at the surface: homeostatic mechanisms of the skin immune system. Life Sci 1996, 58:1485–1507.

    Article  PubMed  CAS  Google Scholar 

  32. De Panfilis G, Manara GC, Ferrari C, et al.: Adhesion molecules on the plasma membrane of epidermal cells. III. Keratinocytes and Langerhans cells constitutively express the lymphocyte function-associated antigen 3. Invest Dermatol 1991, 96:512–517.

    Article  Google Scholar 

  33. Williams IR, Ort RJ, Kupper TS: Keratinocyte expression of B7-1 in transgenic mice amplifies the primary immune response to cutaneous antigens. Proc Natl Acad Sci U S A 1994, 91:12780–12784.

    Article  PubMed  CAS  Google Scholar 

  34. Gaspari AA, Burns RP, Kondo S, et al.: Characterization of the altered cutaneous reactivity of transgenic mice whose keratinocytes overexpress B7-1. Clin Immunol Immunopathol 1998, 86:259–270.

    Article  PubMed  CAS  Google Scholar 

  35. Cao Y, Zhou H, Tao J, et al.: Keratinocytes induce local tolerance to skin graft by activating interleukin-10-secreting T cells in the context of costimulation molecule B7-H1. Transplantation 2003, 75:1390–1396.

    Article  PubMed  CAS  Google Scholar 

  36. De Benedetto A, Mamelak AJ, Wang B, et al.: Variable expression of the B7 costimulatory molecule family on normal human keratinocytes. J Invest Dermatol 2004, 122:A765.

    Google Scholar 

  37. Kurosawa S, Myers A, Chen L, et al.: Expression of the costimulatory molecule B7-H2 (inducible costimulator ligand) by human airway epithelial cells. Am J Respir Cell Mol Biol 2003, 28:563–573. B7-H2 (ICOS-L) is expressed constitutively on human airway epithelial cells, and its expression can be regulated in vitro by various cytokines (IL-4, TNF-γ, IFN-γ). Authors discussed the possibility that B7-H2 might play a role in antigen presentation by epithelial cells.

    Article  PubMed  CAS  Google Scholar 

  38. Gonzalo JA, Tian J, Delaney T, et al.: ICOS is critical for T helper cell mediated lung mucosal inflammatory responses. Nature Immunol 2001, 2:597–604. The authors examined the role of CD28 and ICOS in a model of lung inflammation. They demonstrated that CD28 signal is critical during priming, whereas ICOS regulates Th effector responses. ICOS-mediated signaling contributes to the inflammatory response not only through the regulation of IL-4, but by upregulation of chemokine receptors that determine T-cell migration.

    Article  CAS  Google Scholar 

  39. Okazaki T, Iwai Y, Honjo T: New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 2002, 14:779–782. ICOS and PD-1 appear to be able to regulate autoreactive T and B cells in lymphoid and nonlymphoid tissue. In this review, authors discussed the role played by these newly identified co-receptors in the maintenance of self-tolerance.

    Article  PubMed  CAS  Google Scholar 

  40. Matsumoto K, Inoue H, Nakato T, et al.: B7-DC regulates asthmatic response by and IFN-g-dependent mechanism. J Immunol 2004, 172:2530–2541. Using a murine OVA-induced allergic asthma model, authors discussed the role played by B7-H1 and B7-DC in peripheral immunoregulation. They suggest that B7-DC might attenuate Th2-skewed allergic response by an IFN-γ -dependent, but PD-1-independent, mechanism.

    PubMed  CAS  Google Scholar 

  41. Mempel M, Voelcker V, Kollisch G, et al.: Toll-like receptor expression in human keratinocytes: nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not Toll-like receptor 4 or platelet activating factor receptor dependent. J Invest Dermatol 2003, 121:1389–1396.

    Article  PubMed  CAS  Google Scholar 

  42. Baker BS, Ovigne JM, Powles AV, et al.: Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 2003, 148:670–679.

    Article  PubMed  CAS  Google Scholar 

  43. Lazarus R, Vercelli D, Palmer LJ, et al.: Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease. Immunol Rev 2002, 190:9–25.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Immunology and Allergy, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, 21224-6801, Baltimore, MD, USA

    Clemens Esche MD, Anna de Benedetto MD & Lisa A. Beck MD

Authors
  1. Clemens Esche MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna de Benedetto MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa A. Beck MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Esche, C., de Benedetto, A. & Beck, L.A. Keratinocytes in Atopic dermatitis: Inflammatory signals. Curr Allergy Asthma Rep 4, 276–284 (2004). https://doi.org/10.1007/s11882-004-0071-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-004-0071-8

Keywords

Search

Navigation