Clinical Reviews in Allergy & Immunology

, Volume 41, Issue 3, pp 245–253 | Cite as

A Modular View of Cytokine Networks in Atopic Dermatitis

  • Irit Carmi-Levy
  • Bernhard Homey
  • Vassili Soumelis
Article

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease known for its complex pathophysiology involving several immune pathways. In the lesion, signals from barrier disruption, allergens, and microbial colonization are integrated and transmitted to diverse immune cell types, which initiate and maintain the disease. Cytokines are critical in the allergic intercellular communication networks. This review focuses on up-to-date knowledge on the role of cytokines in AD, including recently described functions as well as novel cellular sources. We propose three modules defined as the cellular source of groups of cytokines: (1) keratinocytes, (2) innate immune cells, and (3) T cells. This view enables to better position the function of novel cytokine players, such as thymic stromal lymphopoetin, IL-21, IL-25, and IL-33, in linking different modules and ultimately leading to the allergic inflammatory phenotype. Persistent efforts in the detailed characterization of cytokine networks will be fundamental for the understanding of the complex pathogenic mechanisms of the disease and for guiding targeted therapeutic interventions.

Keywords

Atopic dermatitis Cytokines Keratinocytes Innate cells T cells 

References

  1. 1.
    Leung DY, Bieber T (2003) Atopic dermatitis. Lancet 361(9352):151–160PubMedCrossRefGoogle Scholar
  2. 2.
    Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA (2004) New insights into atopic dermatitis. J Clin Invest 113(5):651–657PubMedGoogle Scholar
  3. 3.
    Leung DY (2000) Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 105(5):860–876PubMedCrossRefGoogle Scholar
  4. 4.
    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680PubMedGoogle Scholar
  5. 5.
    Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A et al (2005) Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 202(4):541–549PubMedCrossRefGoogle Scholar
  6. 6.
    Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB et al (2005) Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 6(10):1047–1053PubMedCrossRefGoogle Scholar
  7. 7.
    Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M et al (2010) Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol 125(6):1403–1407PubMedCrossRefGoogle Scholar
  8. 8.
    Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S et al (2007) IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med 204(8):1837–1847PubMedCrossRefGoogle Scholar
  9. 9.
    Shimizu M, Matsuda A, Yanagisawa K, Hirota T, Akahoshi M, Inomata N et al (2005) Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis. Hum Mol Genet 14(19):2919–2927PubMedCrossRefGoogle Scholar
  10. 10.
    Moritz DR, Rodewald HR, Gheyselinck J, Klemenz R (1998) The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors. J Immunol 161(9):4866–4874PubMedGoogle Scholar
  11. 11.
    Xu D, Chan WL, Leung BP, Huang F, Wheeler R, Piedrafita D et al (1998) Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J Exp Med 187(5):787–794PubMedCrossRefGoogle Scholar
  12. 12.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490PubMedCrossRefGoogle Scholar
  13. 13.
    Angelova-Fischer I, Fernandez IM, Donnadieu MH, Bulfone-Paus S, Zillikens D, Fischer TW et al (2010) Injury to the stratum corneum induces in vivo expression of human thymic stromal lymphopoietin in the epidermis. J Invest Dermatol 130(10):2505–2507PubMedCrossRefGoogle Scholar
  14. 14.
    Miyata M, Hatsushika K, Ando T, Shimokawa N, Ohnuma Y, Katoh R et al (2008) Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis. Eur J Immunol 38(6):1487–1492PubMedCrossRefGoogle Scholar
  15. 15.
    Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X et al (2007) Cutting edge: proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol 178(6):3373–3377PubMedGoogle Scholar
  16. 16.
    Allakhverdi Z, Comeau MR, Jessup HK, Delespesse G (2009) Thymic stromal lymphopoietin as a mediator of crosstalk between bronchial smooth muscles and mast cells. J Allergy Clin Immunol 123(4):958–960, e2PubMedCrossRefGoogle Scholar
  17. 17.
    Vu AT, Baba T, Chen X, Le TA, Kinoshita H, Xie Y et al (2010) Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2-Toll-like receptor 6 pathway. J Allergy Clin Immunol 126(5):985–993PubMedCrossRefGoogle Scholar
  18. 18.
    Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202(9):1213–1223PubMedCrossRefGoogle Scholar
  19. 19.
    Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S et al (2007) Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 204(2):253–258PubMedCrossRefGoogle Scholar
  20. 20.
    Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ (2005) A role for TSLP in the development of inflammation in an asthma model. J Exp Med 202(6):829–839PubMedCrossRefGoogle Scholar
  21. 21.
    He R, Oyoshi MK, Garibyan L, Kumar L, Ziegler SF, Geha RS (2008) TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc Natl Acad Sci U S A 105(33):11875–11880PubMedCrossRefGoogle Scholar
  22. 22.
    Lu N, Wang YH, Arima K, Hanabuchi S, Liu YJ (2009) TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis. J Exp Med 206(10):2111–2119PubMedCrossRefGoogle Scholar
  23. 23.
    Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S et al (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15(6):985–995PubMedCrossRefGoogle Scholar
  24. 24.
    Angkasekwinai P, Park H, Wang YH, Chang SH, Corry DB, Liu YJ et al (2007) Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med 204(7):1509–1517PubMedCrossRefGoogle Scholar
  25. 25.
    Ikeda K, Nakajima H, Suzuki K, Kagami S, Hirose K, Suto A et al (2003) Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation. Blood 101(9):3594–3596PubMedCrossRefGoogle Scholar
  26. 26.
    Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M (2010) IL-25 in atopic dermatitis: a possible link between Inflammation and skin barrier dysfunction? J Invest Dermatol 131(1):150–157PubMedCrossRefGoogle Scholar
  27. 27.
    Basham TY, Nickoloff BJ, Merigan TC, Morhenn VB (1985) Recombinant gamma interferon differentially regulates class II antigen expression and biosynthesis on cultured normal human keratinocytes. J Interferon Res 5(1):23–32PubMedCrossRefGoogle Scholar
  28. 28.
    O’Regan GM, Irvine AD (2010) The role of filaggrin in the atopic diathesis. Clin Exp Allergy 40(7):965–972PubMedCrossRefGoogle Scholar
  29. 29.
    Allakhverdi Z, Smith DE, Comeau MR, Delespesse G (2007) Cutting edge: the ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol 179(4):2051–2054PubMedGoogle Scholar
  30. 30.
    Mekori YA, Metcalfe DD (2000) Mast cells in innate immunity. Immunol Rev 173:131–140PubMedCrossRefGoogle Scholar
  31. 31.
    Navi D, Saegusa J, Liu FT (2007) Mast cells and immunological skin diseases. Clin Rev Allergy Immunol 33(1–2):144–155PubMedCrossRefGoogle Scholar
  32. 32.
    Schreibelt G, Tel J, Sliepen KH, Benitez-Ribas D, Figdor CG, Adema GJ et al (2010) Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunol Immunother 59(10):1573–1582PubMedCrossRefGoogle Scholar
  33. 33.
    Kang JY, Nan X, Jin MS, Youn SJ, Ryu YH, Mah S et al (2009) Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity 31(6):873–884PubMedCrossRefGoogle Scholar
  34. 34.
    Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG et al (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130(6):1071–1082PubMedCrossRefGoogle Scholar
  35. 35.
    Grewe M, Gyufko K, Schopf E, Krutmann J (1994) Lesional expression of interferon-gamma in atopic eczema. Lancet 343(8888):25–26PubMedCrossRefGoogle Scholar
  36. 36.
    Johnson-Huang LM, McNutt NS, Krueger JG, Lowes MA (2009) Cytokine-producing dendritic cells in the pathogenesis of inflammatory skin diseases. J Clin Immunol 29(3):247–256PubMedCrossRefGoogle Scholar
  37. 37.
    Wang B, Feliciani C, Howell BG, Freed I, Cai Q, Watanabe H et al (2002) Contribution of Langerhans cell-derived IL-18 to contact hypersensitivity. J Immunol 168(7):3303–3308PubMedGoogle Scholar
  38. 38.
    Gracie JA, Robertson SE, McInnes IB (2003) Interleukin-18. J Leukoc Biol 73(2):213–224PubMedCrossRefGoogle Scholar
  39. 39.
    Homey B, Steinhoff M, Ruzicka T, Leung DY (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118(1):178–189PubMedCrossRefGoogle Scholar
  40. 40.
    Nakanishi K, Tsutsui H, Yoshimoto T (2010) Importance of IL-18-induced super Th1 cells for the development of allergic inflammation. Allergol Int 59(2):137–141PubMedCrossRefGoogle Scholar
  41. 41.
    Sugimoto T, Ishikawa Y, Yoshimoto T, Hayashi N, Fujimoto J, Nakanishi K (2004) Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J Exp Med 199(4):535–545PubMedCrossRefGoogle Scholar
  42. 42.
    Yoshimoto T, Tsutsui H, Tominaga K, Hoshino K, Okamura H, Akira S et al (1999) IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc Natl Acad Sci U S A 96(24):13962–13966PubMedCrossRefGoogle Scholar
  43. 43.
    Yoshimoto T, Min B, Sugimoto T, Hayashi N, Ishikawa Y, Sasaki Y et al (2003) Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+ T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice. J Exp Med 197(8):997–1005PubMedCrossRefGoogle Scholar
  44. 44.
    Matsui K, Wirotesangthong M, Nishikawa A (2008) Peptidoglycan from Staphylococcus aureus induces IL-4 production from murine spleen cells via an IL-18-dependent mechanism. Int Arch Allergy Immunol 146(3):262–266PubMedCrossRefGoogle Scholar
  45. 45.
    Swain SL, Weinberg AD, English M, Huston G (1990) IL-4 directs the development of Th2-like helper effectors. J Immunol 145(11):3796–3806PubMedGoogle Scholar
  46. 46.
    Renauld JC (2001) New insights into the role of cytokines in asthma. J Clin Pathol 54(8):577–589PubMedCrossRefGoogle Scholar
  47. 47.
    Hamelmann E, Gelfand EW (2001) IL-5-induced airway eosinophilia—the key to asthma? Immunol Rev 179:182–191PubMedCrossRefGoogle Scholar
  48. 48.
    Jin H, Oyoshi MK, Le Y, Bianchi T, Koduru S, Mathias CB et al (2009) IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice. J Clin Invest 119(1):47–60PubMedGoogle Scholar
  49. 49.
    Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M et al (2002) Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J Exp Med 196(7):969–977PubMedCrossRefGoogle Scholar
  50. 50.
    Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152):480–483PubMedCrossRefGoogle Scholar
  51. 51.
    Sarra M, Monteleone I, Stolfi C, Fantini MC, Sileri P, Sica G et al (2010) Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases. Inflamm Bowel Dis 16(8):1332–1339PubMedGoogle Scholar
  52. 52.
    Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS et al (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 173(1):68–78PubMedGoogle Scholar
  53. 53.
    Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT et al (2007) IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 178(2):732–739PubMedGoogle Scholar
  54. 54.
    Costanzo A, Chimenti MS, Botti E, Caruso R, Sarra M, Monteleone G (2010) IL-21 in the pathogenesis and treatment of skin diseases. J Dermatol Sci 60(2):61–66PubMedCrossRefGoogle Scholar
  55. 55.
    Konforte D, Simard N, Paige CJ (2009) IL-21: an executor of B cell fate. J Immunol 182(4):1781–1787PubMedCrossRefGoogle Scholar
  56. 56.
    Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR et al (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5(7):752–760PubMedCrossRefGoogle Scholar
  57. 57.
    Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L et al (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 117(2):411–417PubMedCrossRefGoogle Scholar
  58. 58.
    Bilsborough J, Leung DY, Maurer M, Howell M, Boguniewicz M, Yao L et al (2006) IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol 117(2):418–425PubMedCrossRefGoogle Scholar
  59. 59.
    Raap U, Wichmann K, Bruder M, Stander S, Wedi B, Kapp A et al (2008) Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 122(2):421–423PubMedCrossRefGoogle Scholar
  60. 60.
    Cheung PF, Wong CK, Ho AW, Hu S, Chen DP, Lam CW (2010) Activation of human eosinophils and epidermal keratinocytes by Th2 cytokine IL-31: implication for the immunopathogenesis of atopic dermatitis. Int Immunol 22(6):453–467PubMedCrossRefGoogle Scholar
  61. 61.
    Antonysamy MA, Fanslow WC, Fu F, Li W, Qian S, Troutt AB et al (1999) Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol 162(1):577–584PubMedGoogle Scholar
  62. 62.
    Milovanovic M, Drozdenko G, Weise C, Babina M, Worm M (2010) Interleukin-17A promotes IgE production in human B cells. J Invest Dermatol 130(11):2621–2628PubMedCrossRefGoogle Scholar
  63. 63.
    Toda M, Leung DY, Molet S, Boguniewicz M, Taha R, Christodoulopoulos P et al (2003) Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol 111(4):875–881PubMedCrossRefGoogle Scholar
  64. 64.
    Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y (2008) Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 128(11):2625–2630PubMedCrossRefGoogle Scholar
  65. 65.
    Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE et al (2008) Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol 181(10):7420–7427PubMedGoogle Scholar
  66. 66.
    Lee FE, Georas SN, Beck LA (2010) IL-17: important for host defense, autoimmunity, and allergy? J Invest Dermatol 130(11):2540–2542PubMedCrossRefGoogle Scholar
  67. 67.
    Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A (2003) IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol 170(4):2106–2112PubMedGoogle Scholar
  68. 68.
    Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R et al (2006) Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25(2):309–318PubMedCrossRefGoogle Scholar
  69. 69.
    Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10(7):479–489PubMedCrossRefGoogle Scholar
  70. 70.
    Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J et al (2010) Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol 184(7):3336–3340PubMedCrossRefGoogle Scholar
  71. 71.
    Wang YH, Voo KS, Liu B, Chen CY, Uygungil B, Spoede W et al (2010) A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med 207(11):2479–2491PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Irit Carmi-Levy
    • 1
    • 2
  • Bernhard Homey
    • 3
  • Vassili Soumelis
    • 1
    • 2
    • 4
  1. 1.INSERM U932ParisFrance
  2. 2.Department of ImmunologyInstitut CurieParisFrance
  3. 3.Department of DermatologyUniversity Hospital DüsseldorfDüsseldorfGermany
  4. 4.Center of Clinical Investigations, CIC-BT-507Curie-IGRParisFrance

Personalised recommendations