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Seminars in Immunopathology

, Volume 38, Issue 1, pp 29–43 | Cite as

The role of innate immune signaling in the pathogenesis of atopic dermatitis and consequences for treatments

  • Yuliya Skabytska
  • Susanne Kaesler
  • Thomas Volz
  • Tilo Biedermann
Review

Abstract

The skin is the largest organ at the interface between the environment and the host. Consequently, the skin plays a central role in mounting effective host defense. In addition to pathogens, the microbiota and the host immune system are in permanent contact and communication via the skin. Consequences of this permanent interaction are a unique and partly symbiotic relationship, a tight interdependence between these partners, and also a functional “setting the clock,” in which, in the healthy steady state, an induction of protective responses to pathogens is guaranteed. At the same time, commensal microbes contribute to the alertness of the immune system and to the maintenance of immune tolerance. Atopic dermatitis (AD) is a chronic inflammatory skin disease based on a complex genetic trait with defects in cutaneous barrier, in stabilizing skin integrity. Most of AD patients develop deviated innate and adaptive immune responses. As a result, increased susceptibility to cutaneous infection is found in AD patients, and the interactions between these microbes and the skin participate in the development of chronic cutaneous inflammation. The role of the adaptive immune system was characterized in much detail, less though the contribution of innate immunity to AD pathogenesis. It is rather recent evidence that demonstrates a dominant role of components of the innate immune system not only for protecting from microbial invasion but also by orchestrating chronic skin inflammation. In this review we discuss the role of innate immune signaling and consecutive immune networks important for the pathogenesis and management of AD.

Keywords

Cutaneous inflammation Atopic dermatitis TLR2 

References

  1. 1.
    Novak N, Bieber T, Leung DY (2003) Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol 112:S128–S139PubMedCrossRefGoogle Scholar
  2. 2.
    Eyerich K, Eyerich S, Biedermann T (2015) The multi-modal immune pathogenesis of atopic eczema. Trends ImmunolGoogle Scholar
  3. 3.
    Elias PM (2005) Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125:183–200PubMedGoogle Scholar
  4. 4.
    Proksch E, Brandner JM, Jensen JM (2008) The skin: an indispensable barrier. Exp Dermatol 17:1063–1072PubMedCrossRefGoogle Scholar
  5. 5.
    Wood LC, Jackson SM, Elias PM, Grunfeld C, Feingold KR (1992) Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J Clin Invest 90:482–487PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Kuo IH, Yoshida T, De Benedetto A, Beck LA (2013) The cutaneous innate immune response in patients with atopic dermatitis. J Allergy Clin Immunol 131:266–278PubMedCrossRefGoogle Scholar
  7. 7.
    Gupta J, Grube E, Ericksen MB, Stevenson MD, Lucky AW, Sheth AP, Assa’ad AH, Khurana Hershey GK (2008) Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity. J Allergy Clin Immunol 121:725–30.e2PubMedCrossRefGoogle Scholar
  8. 8.
    Giustizieri ML, Mascia F, Frezzolini A, De Pita O, Chinni LM, Giannetti A, Girolomoni G, Pastore S (2001) 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 107:871–877PubMedCrossRefGoogle Scholar
  9. 9.
    Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Hogh JK, Hellgren LI, Jemec GB, Agner T, Weidinger S (2010) Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 65:911–918PubMedCrossRefGoogle Scholar
  10. 10.
    Agrawal R, Woodfolk JA (2014) Skin barrier defects in atopic dermatitis. Curr Allergy Asthma Rep 14:433PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Miajlovic H, Fallon PG, Irvine AD, Foster TJ (2010) Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus. J Allergy Clin Immunol 126:1184–90.e3PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38:441–446PubMedCrossRefGoogle Scholar
  13. 13.
    Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, Gruber C, Lau S, Worm M, Keil T, Kurek M, Zaluga E, Wahn U, Lee YA (2006) Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 118:866–871PubMedCrossRefGoogle Scholar
  14. 14.
    Seguchi T, Cui CY, Kusuda S, Takahashi M, Aisu K, Tezuka T (1996) Decreased expression of filaggrin in atopic skin. Arch Dermatol Res 288:442–446PubMedCrossRefGoogle Scholar
  15. 15.
    Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY (2007) Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 120:150–155PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Cho SH, Strickland I, Boguniewicz M, Leung DY (2001) Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 108:269–274PubMedCrossRefGoogle Scholar
  17. 17.
    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 119:433–439PubMedCrossRefGoogle Scholar
  18. 18.
    Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM (2003) pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 121:345–353PubMedCrossRefGoogle Scholar
  19. 19.
    Wanke I, Skabytska Y, Kraft B, Peschel A, Biedermann T, Schittek B (2013) Staphylococcus aureus skin colonization is promoted by barrier disruption and leads to local inflammation. Exp Dermatol 22:153–155PubMedCrossRefGoogle Scholar
  20. 20.
    Afshar M, Gallo RL (2013) Innate immune defense system of the skin. Vet Dermatol 24:32–8.e8-9PubMedCrossRefGoogle Scholar
  21. 21.
    Schauber J, Gallo RL (2008) Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 122:261–266PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Schroder JM, Harder J (1999) Human beta-defensin-2. Int J Biochem Cell Biol 31:645–651PubMedCrossRefGoogle Scholar
  23. 23.
    Harder J, Bartels J, Christophers E, Schroder JM (2001) Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707–5713PubMedCrossRefGoogle Scholar
  24. 24.
    Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347:1151–1160PubMedCrossRefGoogle Scholar
  25. 25.
    Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE, Leung DY (2006) Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24:341–348PubMedCrossRefGoogle Scholar
  26. 26.
    Rieg S, Steffen H, Seeber S, Humeny A, Kalbacher H, Dietz K, Garbe C, Schittek B (2005) Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo. J Immunol 174:8003–8010PubMedCrossRefGoogle Scholar
  27. 27.
    Homey B, Steinhoff M, Ruzicka T, Leung DY (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118:178–189PubMedCrossRefGoogle Scholar
  28. 28.
    Hamid Q, Boguniewicz M, Leung DY (1994) Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 94:870–876PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Spergel JM, Mizoguchi E, Oettgen H, Bhan AK, Geha RS (1999) Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J Clin Invest 103:1103–1111PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Biedermann T, Schwarzler C, Lametschwandtner G, Thoma G, Carballido-Perrig N, Kund J, de Vries JE, Rot A, Carballido JM (2002) Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo. Eur J Immunol 32:3171–3180PubMedCrossRefGoogle Scholar
  31. 31.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Guenova E, Skabytska Y, Hoetzenecker W, Weindl G, Sauer K, Tham M, Kim KW, Park JH, Seo JH, Ignatova D, Cozzio A, Levesque MP, Volz T, Koberle M, Kaesler S, Thomas P, Mailhammer R, Ghoreschi K, Schakel K, Amarov B, Eichner M, Schaller M, Clark RA, Rocken M, Biedermann T (2015) IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci U S A 112:2163–2168PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Biedermann T, Mailhammer R, Mai A, Sander C, Ogilvie A, Brombacher F, Maier K, Levine AD, Rocken M (2001) Reversal of established delayed type hypersensitivity reactions following therapy with IL-4 or antigen-specific Th2 cells. Eur J Immunol 31:1582–1591PubMedCrossRefGoogle Scholar
  34. 34.
    Cho SH, Strickland I, Tomkinson A, Fehringer AP, Gelfand EW, Leung DY (2001) Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model. J Invest Dermatol 116:658–663PubMedCrossRefGoogle Scholar
  35. 35.
    Hatano Y, Terashi H, Arakawa S, Katagiri K (2005) 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 124:786–792PubMedCrossRefGoogle Scholar
  36. 36.
    Kurahashi R, Hatano Y, Katagiri K (2008) IL-4 suppresses the recovery of cutaneous permeability barrier functions in vivo. J Invest Dermatol 128:1329–1331PubMedCrossRefGoogle Scholar
  37. 37.
    Guzik TJ, Bzowska M, Kasprowicz A, Czerniawska-Mysik G, Wojcik K, Szmyd D, Adamek-Guzik T, Pryjma J (2005) Persistent skin colonization with Staphylococcus aureus in atopic dermatitis: relationship to clinical and immunological parameters. Clin Exp Allergy 35:448–455PubMedCrossRefGoogle Scholar
  38. 38.
    Biedermann T (2006) Dissecting the role of infections in atopic dermatitis. Acta Derm Venereol 86:99–109PubMedGoogle Scholar
  39. 39.
    Kaesler S, Volz T, Skabytska Y, Koberle M, Hein U, Chen KM, Guenova E, Wolbing F, Rocken M, Biedermann T (2014) Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol 134:92–99PubMedCrossRefGoogle Scholar
  40. 40.
    Volz T, Kaesler S, Biedermann T (2011) Innate immune sensing 2.0—from linear activation pathways to fine tuned and regulated innate immune networks. Exp Dermatol 21:61–69CrossRefGoogle Scholar
  41. 41.
    Medzhitov R, Janeway CA Jr (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295–298PubMedCrossRefGoogle Scholar
  42. 42.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedCrossRefGoogle Scholar
  43. 43.
    Pivarcsi A, Kemeny L, Dobozy A (2004) Innate immune functions of the keratinocytes. A review. Acta Microbiol Immunol Hung 51:303–310PubMedCrossRefGoogle Scholar
  44. 44.
    Volz T, Skabytska Y, Guenova E, Chen KM, Frick JS, Kirschning CJ, Kaesler S, Rocken M, Biedermann T (2014) Nonpathogenic bacteria alleviating atopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells. J Invest Dermatol 134:96–104PubMedCrossRefGoogle Scholar
  45. 45.
    Volz T, Nega M, Buschmann J, Kaesler S, Guenova E, Peschel A, Rocken M, Gotz F, Biedermann T (2010) Natural Staphylococcus aureus-derived peptidoglycan fragments activate NOD2 and act as potent costimulators of the innate immune system exclusively in the presence of TLR signals. FASEB J 24:4089–4102PubMedCrossRefGoogle Scholar
  46. 46.
    Kupper TS, Fuhlbrigge RC (2004) Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol 4:211–222PubMedCrossRefGoogle Scholar
  47. 47.
    Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825PubMedCrossRefGoogle Scholar
  48. 48.
    Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95PubMedCrossRefGoogle Scholar
  49. 49.
    Brikos C, O’Neill LA (2008) Signalling of toll-like receptors. Handb Exp Pharmacol 21–50Google Scholar
  50. 50.
    Zahringer U, Lindner B, Inamura S, Heine H, Alexander C (2008) TLR2—promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology 213:205–224PubMedCrossRefGoogle Scholar
  51. 51.
    Stoll H, Dengjel J, Nerz C, Götz F (2005) Staphylococcus aureus deficient in lipidation of prelipoproteins is attenuated in growth and immune activation. Infect Immun 73:2411–2423PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hashimoto M, Tawaratsumida K, Kariya H, Aoyama K, Tamura T, Suda Y (2006) Lipoprotein is a predominant Toll-like receptor 2 ligand in Staphylococcus aureus cell wall components. Int Immunol 18:355–362PubMedCrossRefGoogle Scholar
  53. 53.
    Kurokawa K, Lee H, Roh KB, Asanuma M, Kim YS, Nakayama H, Shiratsuchi A, Choi Y, Takeuchi O, Kang HJ, Dohmae N, Nakanishi Y, Akira S, Sekimizu K, Lee BL (2009) The triacylated ATP binding cluster transporter substrate-binding lipoprotein of Staphylococcus aureus functions as a native ligand for toll-like receptor 2. J Biol Chem 284:8406–8411PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Takeuchi O, Hoshino K, Akira S (2000) Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 165:5392–5396PubMedCrossRefGoogle Scholar
  55. 55.
    Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97:13766–13771PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, Lee H, Lee JO (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082PubMedCrossRefGoogle Scholar
  57. 57.
    Buwitt-Beckmann U, Heine H, Wiesmuller KH, Jung G, Brock R, Akira S, Ulmer AJ (2005) Toll-like receptor 6-independent signaling by diacylated lipopeptides. Eur J Immunol 35:282–289PubMedCrossRefGoogle Scholar
  58. 58.
    Triantafilou M, Gamper FG, Haston RM, Mouratis MA, Morath S, Hartung T, Triantafilou K (2006) Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J Biol Chem 281:31002–31011PubMedCrossRefGoogle Scholar
  59. 59.
    Triantafilou M, Manukyan M, Mackie A, Morath S, Hartung T, Heine H, Triantafilou K (2004) Lipoteichoic acid and toll-like receptor 2 internalization and targeting to the Golgi are lipid raft-dependent. J Biol Chem 279:40882–40889PubMedCrossRefGoogle Scholar
  60. 60.
    Farhat K, Riekenberg S, Heine H, Debarry J, Lang R, Mages J, Buwitt-Beckmann U, Roschmann K, Jung G, Wiesmuller KH, Ulmer AJ (2008) Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. J Leukoc Biol 83:692–701PubMedCrossRefGoogle Scholar
  61. 61.
    Nakata T, Yasuda M, Fujita M, Kataoka H, Kiura K, Sano H, Shibata K (2006) CD14 directly binds to triacylated lipopeptides and facilitates recognition of the lipopeptides by the receptor complex of Toll-like receptors 2 and 1 without binding to the complex. Cell Microbiol 8:1899–1909PubMedCrossRefGoogle Scholar
  62. 62.
    Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, Sovath S, Shamel L, Hartung T, Zahringer U, Beutler B (2005) CD36 is a sensor of diacylglycerides. Nature 433:523–527PubMedCrossRefGoogle Scholar
  63. 63.
    Thompson CM, Holden TD, Rona G, Laxmanan B, Black RA, O’Keefe GE, Wurfel MM (2014) Toll-like receptor 1 polymorphisms and associated outcomes in sepsis after traumatic injury: a candidate gene association study. Ann Surg 259:179–185PubMedCrossRefGoogle Scholar
  64. 64.
    Moreira AP, Cavassani KA, Ismailoglu UB, Hullinger R, Dunleavy MP, Knight DA, Kunkel SL, Uematsu S, Akira S, Hogaboam CM (2011) The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A. J Clin Invest 121:4420–4432PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Zhang Y, Jiang T, Yang X, Xue Y, Wang C, Liu J, Zhang X, Chen Z, Zhao M, Li JC (2013) Toll-like receptor −1, −2, and −6 polymorphisms and pulmonary tuberculosis susceptibility: a systematic review and meta-analysis. PLoS One 8, e63357PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Barrenschee M, Lex D, Uhlig S (2010) Effects of the TLR2 agonists MALP-2 and Pam3Cys in isolated mouse lungs. PLoS One 5, e13889PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Morgan ME, Koelink PJ, Zheng B, den Brok MH, van de Kant HJ, Verspaget HW, Folkerts G, Adema GJ, Kraneveld AD (2014) Toll-like receptor 6 stimulation promotes T-helper 1 and 17 responses in gastrointestinal-associated lymphoid tissue and modulates murine experimental colitis. Mucosal Immunol 7:1266–1277PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Skabytska Y, Wolbing F, Gunther C, Koberle M, Kaesler S, Chen KM, Guenova E, Demircioglu D, Kempf WE, Volz T, Rammensee HG, Schaller M, Rocken M, Gotz F, Biedermann T (2014) Cutaneous innate immune sensing of Toll-like receptor 2–6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity 41:762–775PubMedCrossRefGoogle Scholar
  69. 69.
    Skabytska Y, Biedermann T (2015) Cutaneous bacteria induce immunosuppression. Oncotarget 6:30441–30442PubMedGoogle Scholar
  70. 70.
    Kurokawa K, Kim MS, Ichikawa R, Ryu KH, Dohmae N, Nakayama H, Lee BL (2012) Environment-mediated accumulation of diacyl lipoproteins over their triacyl counterparts in Staphylococcus aureus. J Bacteriol 194:3299–3306PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Girardin SE, Philpott DJ (2004) Mini-review: the role of peptidoglycan recognition in innate immunity. Eur J Immunol 34:1777–1782PubMedCrossRefGoogle Scholar
  72. 72.
    Harder J, Nunez G (2009) Functional expression of the intracellular pattern recognition receptor NOD1 in human keratinocytes. J Invest Dermatol 129:1299–1302PubMedCrossRefGoogle Scholar
  73. 73.
    Weidinger S, Klopp N, Rummler L, Wagenpfeil S, Novak N, Baurecht HJ, Groer W, Darsow U, Heinrich J, Gauger A, Schafer T, Jakob T, Behrendt H, Wichmann HE, Ring J, Illig T (2005) Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 116:177–184PubMedCrossRefGoogle Scholar
  74. 74.
    Hruz P, Zinkernagel AS, Jenikova G, Botwin GJ, Hugot JP, Karin M, Nizet V, Eckmann L (2009) NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation. Proc Natl Acad Sci U S A 106:12873–12878PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820PubMedCrossRefGoogle Scholar
  76. 76.
    Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S (2003) Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 197:1119–1124PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Reid DM, Gow NA, Brown GD (2009) Pattern recognition: recent insights from Dectin-1. Curr Opin Immunol 21:30–37PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA (2000) A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68:6398–6401PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz M, Werfel T, Herz U, Heeg K, Neumaier M, Renz H (2004) The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 113:565–567PubMedCrossRefGoogle Scholar
  80. 80.
    Kuo IH, Carpenter-Mendini A, Yoshida T, McGirt LY, Ivanov AI, Barnes KC, Gallo RL, Borkowski AW, Yamasaki K, Leung DY, Georas SN, De Benedetto A, Beck LA (2013) Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair. J Invest Dermatol 133:988–998PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Niebuhr M, Lutat C, Sigel S, Werfel T (2009) Impaired TLR-2 expression and TLR-2-mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy 64:1580–1587PubMedCrossRefGoogle Scholar
  82. 82.
    Mrabet-Dahbi S, Dalpke AH, Niebuhr M, Frey M, Draing C, Brand S, Heeg K, Werfel T, Renz H (2008) The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 121:1013–1019PubMedCrossRefGoogle Scholar
  83. 83.
    Potaczek DP, Nastalek M, Okumura K, Wojas-Pelc A, Undas A, Nishiyama C (2011) An association of TLR2-16934A >T polymorphism and severity/phenotype of atopic dermatitis. J Eur Acad Dermatol Venereol 25:715–721PubMedCrossRefGoogle Scholar
  84. 84.
    Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G (2009) Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 64:1608–1615PubMedCrossRefGoogle Scholar
  85. 85.
    Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P, Hamid Q, Kapp A, Leung DY, Lipozencic J, Luger TA, Muraro A, Novak N, Platts-Mills TA, Rosenwasser L, Scheynius A, Simons FE, Spergel J, Turjanmaa K, Wahn U, Weidinger S, Werfel T, Zuberbier T (2006) Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol 118:152–169PubMedCrossRefGoogle Scholar
  86. 86.
    Weidinger S, Novak N, Klopp N, Baurecht H, Wagenpfeil S, Rummler L, Ring J, Behrendt H, Illig T (2006) Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema. J Allergy Clin Immunol 118:277–279PubMedCrossRefGoogle Scholar
  87. 87.
    Kabesch M, Peters W, Carr D, Leupold W, Weiland SK, von Mutius E (2003) Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 111:813–817PubMedCrossRefGoogle Scholar
  88. 88.
    Novak N, Yu CF, Bussmann C, Maintz L, Peng WM, Hart J, Hagemann T, Diaz-Lacava A, Baurecht HJ, Klopp N, Wagenpfeil S, Behrendt H, Bieber T, Ring J, Illig T, Weidinger S (2007) Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 62:766–772PubMedCrossRefGoogle Scholar
  89. 89.
    Grice EA, Kong HH, Renaud G, Young AC, Bouffard GG, Blakesley RW, Wolfsberg TG, Turner ML, Segre JA (2008) A diversity profile of the human skin microbiota. Genome Res 18:1043–1050PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC, Bouffard GG, Blakesley RW, Murray PR, Green ED, Turner ML, Segre JA (2009) Topographical and temporal diversity of the human skin microbiome. Science 324:1190–1192PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Consortium HMP (2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207–214CrossRefGoogle Scholar
  92. 92.
    Grice EA, Segre JA (2011) The skin microbiome. Nat Rev Microbiol 9:244–253PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Fitz-Gibbon S, Tomida S, Chiu BH, Nguyen L, Du C, Liu M, Elashoff D, Erfe MC, Loncaric A, Kim J, Modlin RL, Miller JF, Sodergren E, Craft N, Weinstock GM, Li H (2013) Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 133:2152–2160PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Gallo RL, Hooper LV (2012) Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 12:503–516PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Cogen AL, Yamasaki K, Sanchez KM, Dorschner RA, Lai Y, MacLeod DT, Torpey JW, Otto M, Nizet V, Kim JE, Gallo RL (2010) Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. J Invest Dermatol 130:192–200PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Wang R, Braughton KR, Kretschmer D, Bach TH, Queck SY, Li M, Kennedy AD, Dorward DW, Klebanoff SJ, Peschel A, DeLeo FR, Otto M (2007) Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med 13:1510–1514PubMedCrossRefGoogle Scholar
  97. 97.
    Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K, Agata T, Mizunoe Y (2010) Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 465:346–349PubMedCrossRefGoogle Scholar
  98. 98.
    Lai Y, Cogen AL, Radek KA, Park HJ, Macleod DT, Leichtle A, Ryan AF, Di Nardo A, Gallo RL (2010) Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J Invest Dermatol 130:2211–2221PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, Cogen AL, Wu ZR, Hooper LV, Schmidt RR, von Aulock S, Radek KA, Huang CM, Ryan AF, Gallo RL (2009) Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med 15:1377–1382PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wanke I, Steffen H, Christ C, Krismer B, Gotz F, Peschel A, Schaller M, Schittek B (2011) Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways. J Invest Dermatol 131:382–390PubMedCrossRefGoogle Scholar
  101. 101.
    Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, Deming C, Quinones M, Koo L, Conlan S, Spencer S, Hall JA, Dzutsev A, Kong H, Campbell DJ, Trinchieri G, Segre JA, Belkaid Y (2012) Compartmentalized control of skin immunity by resident commensals. Science 337:1115–1119PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Belkaid Y, Hand TW (2014) Role of the microbiota in immunity and inflammation. Cell 157:121–141PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Biedermann T, Skabytska Y, Kaesler S, Volz T (2015) Regulation of T cell immunity in atopic dermatitis by microbes: the Yin and Yang of cutaneous inflammation. Front Immunol 6:353PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA (2012) Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 22:850–859PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Panduru M, Panduru NM, Salavastru CM, Tiplica GS (2015) Probiotics and primary prevention of atopic dermatitis: a meta-analysis of randomized controlled studies. J Eur Acad Dermatol Venereol 29:232–242PubMedCrossRefGoogle Scholar
  106. 106.
    Wickens K, Stanley TV, Mitchell EA, Barthow C, Fitzharris P, Purdie G, Siebers R, Black PN, Crane J (2013) Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Clin Exp Allergy 43:1048–1057PubMedCrossRefGoogle Scholar
  107. 107.
    Kalliomaki M, Salminen S, Poussa T, Isolauri E (2007) Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol 119:1019–1021PubMedCrossRefGoogle Scholar
  108. 108.
    West CE, Hammarstrom ML, Hernell O (2013) Probiotics in primary prevention of allergic disease--follow-up at 8–9 years of age. Allergy 68:1015–1020PubMedCrossRefGoogle Scholar
  109. 109.
    Kalliomaki M, Salminen S, Poussa T, Arvilommi H, Isolauri E (2003) Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 361:1869–1871PubMedCrossRefGoogle Scholar
  110. 110.
    Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TM, Zaat BA, Yazdanbakhsh M, Wierenga EA, van Kooyk Y, Kapsenberg ML (2005) Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol 115:1260–1267PubMedCrossRefGoogle Scholar
  111. 111.
    Iemoli E, Trabattoni D, Parisotto S, Borgonovo L, Toscano M, Rizzardini G, Clerici M, Ricci E, Fusi A, De Vecchi E, Piconi S, Drago L (2012) Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. J Clin Gastroenterol 46(Suppl):S33–S40PubMedCrossRefGoogle Scholar
  112. 112.
    Lee J, Seto D, Bielory L (2008) Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol 121(116–21), e11PubMedGoogle Scholar
  113. 113.
    Gueniche A, Knaudt B, Schuck E, Volz T, Bastien P, Martin R, Röcken M, Breton L, Biedermann T (2008) Effects of nonpathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic dermatitis: a prospective, randomized, double-blind, placebo-controlled clinical study. Br J Dermatol 159:1357–1363PubMedCrossRefGoogle Scholar
  114. 114.
    Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K, Laatikainen T, Karisola P, Auvinen P, Paulin L, Makela MJ, Vartiainen E, Kosunen TU, Alenius H, Haahtela T (2012) Environmental biodiversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci U S A 109:8334–8339PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Monti G, Tonetto P, Mostert M, Oggero R (1996) Staphylococcus aureus skin colonization in infants with atopic dermatitis. Dermatology 193:83–87PubMedCrossRefGoogle Scholar
  116. 116.
    Leung AD, Schiltz AM, Hall CF, Liu AH (2008) Severe atopic dermatitis is associated with a high burden of environmental Staphylococcus aureus. Clin Exp Allergy 38:789–793PubMedCrossRefGoogle Scholar
  117. 117.
    Foster TJ, Höök M (1998) Surface protein adhesins of Staphylococcus aureus. Trends Microbiol 6:484–488PubMedCrossRefGoogle Scholar
  118. 118.
    Bunikowski R, Mielke ME, Skarabis H, Worm M, Anagnostopoulos I, Kolde G, Wahn U, Renz H (2000) Evidence for a disease-promoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 105:814–819PubMedCrossRefGoogle Scholar
  119. 119.
    Travers JB, Kozman A, Mousdicas N, Saha C, Landis M, Al-Hassani M, Yao W, Yao Y, Hyatt AM, Sheehan MP, Haggstrom AN, Kaplan MH (2010) Infected atopic dermatitis lesions contain pharmacologic amounts of lipoteichoic acid. J Allergy Clin Immunol 125(146–52):e1–e2PubMedGoogle Scholar
  120. 120.
    Cleveland MG, Gorham JD, Murphy TL, Tuomanen E, Murphy KM (1996) Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway. Infect Immun 64:1906–1912PubMedPubMedCentralGoogle Scholar
  121. 121.
    Boguniewicz M, Sampson H, Leung SB, Harbeck R, Leung DY (2001) Effects of cefuroxime axetil on Staphylococcus aureus colonization and superantigen production in atopic dermatitis. J Allergy Clin Immunol 108:651–652PubMedCrossRefGoogle Scholar
  122. 122.
    Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T, Rocklin R, Ming JE, Ren H, Kao R, Simpson E, Ardeleanu M, Weinstein SP, Pirozzi G, Guttman-Yassky E, Suarez-Farinas M, Hager MD, Stahl N, Yancopoulos GD, Radin AR (2014) Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 371:130–139PubMedCrossRefGoogle Scholar
  123. 123.
    Heil PM, Maurer D, Klein B, Hultsch T, Stingl G (2010) Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course - a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges 8:990–998PubMedGoogle Scholar
  124. 124.
    Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, Mitsui H, Cardinale I, de Guzman SC, Krueger JG, Guttman-Yassky E (2012) Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 130:1344–1354PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, Haugen HS, Maurer M, Harder B, Johnston J, Bort S, Mudri S, Kuijper JL, Bukowski T, Shea P, Dong DL, Dasovich M, Grant FJ, Lockwood L, Levin SD, LeCiel C, Waggie K, Day H, Topouzis S, Kramer J, Kuestner R, Chen Z, Foster D, Parrish-Novak J, Gross JA (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5:752–760PubMedCrossRefGoogle Scholar
  126. 126.
    Werfel T, Biedermann T (2015) Current novel approaches in systemic therapy of atopic dermatitis: specific inhibition of cutaneous Th2 polarized inflammation and itch. Curr Opin Allergy Clin Immunol 15:446–452PubMedCrossRefGoogle Scholar
  127. 127.
    Fedenko ES, Elisyutina OG, Filimonova TM, Boldyreva MN, Burmenskaya OV, Rebrova OY, Yarilin AA, Khaitov RM (2011) Cytokine gene expression in the skin and peripheral blood of atopic dermatitis patients and healthy individuals. Self Nonself 2:120–124PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Esparza-Gordillo J, Schaarschmidt H, Liang L, Cookson W, Bauerfeind A, Lee-Kirsch MA, Nemat K, Henderson J, Paternoster L, Harper JI, Mangold E, Nothen MM, Ruschendorf F, Kerscher T, Marenholz I, Matanovic A, Lau S, Keil T, Bauer CP, Kurek M, Ciechanowicz A, Macek M, Franke A, Kabesch M, Hubner N, Abecasis G, Weidinger S, Moffatt M, Lee YA (2013) A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. J Allergy Clin Immunol 132:371–377PubMedCrossRefGoogle Scholar
  129. 129.
    Navarini AA, French LE, Hofbauer GF (2011) Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol 128:1128–1130PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Yuliya Skabytska
    • 1
    • 2
  • Susanne Kaesler
    • 1
    • 2
  • Thomas Volz
    • 1
  • Tilo Biedermann
    • 1
  1. 1.Department of Dermatology and Allergology, TUM School of MedicineTechnische Universität MünchenMunichGermany
  2. 2.Department of DermatologyEberhard-Karls-University TübingenTübingenGermany

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