Skip to main content

The Role of Toll-Like Receptors in Host Defenses and Their Relevance to Dermatologic Diseases

American Journal of Clinical Dermatology volume 11, pages 1–10 (2010)Cite this article

Abstract

The family of toll-like receptors (TLRs) plays a central role in the cutaneous immune defense system. To date, different TLRs have been found on several major cell populations of the skin, such as keratinocytes, fibroblasts, antigen-presenting cells, and melanocytes.

Activation of TLRs leads, via different intracellular signaling pathways, to the production of pro-inflammatory stimuli, and is considered a danger signal that should transform the skin in to the functional state of defense. However, TLRs have also been implicated in tissue homeostasis and renewal.

Within the group of TLRs, two types have been identified: surface-expressed TLRs, which are predominantly active against bacterial cell wall compounds; and intracellular receptors, which preferentially recognize virus-associated pattern molecules. In addition, surface-expressed receptors trigger phagocytotic and maturation signals, while the intracellular TLRs lead to the induction of antiviral genes.

Our review aims to outline the importance of TLRs in the pathogenesis of numerous skin diseases and the potential of TLR agonists as a treatment option for various skin diseases.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

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

Fig. 1
Table I
Table II

References

  1. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124 (4): 783–801

    CAS  PubMed  Google Scholar 

  2. Kawai T, Akira S. TLR signaling. Cell Death Differ 2006; 13 (5): 816–25

    CAS  PubMed  Google Scholar 

  3. 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 (6): 1389–96

    CAS  PubMed  Google Scholar 

  4. Kollisch G, Kalali BN, Voelcker V, et al. Various members of the toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology 2005; 114 (4): 531–41

    PubMed Central  PubMed  Google Scholar 

  5. Miller LS, Sorensen OE, Liu PT, et al. TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J Immunol 2005; 174 (10): 6137–43

    CAS  PubMed  Google Scholar 

  6. Lebre MC, van der Aar AM, van Baarsen L, et al. Human keratinocytes express functional toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 2007; 127: 331–41

    CAS  PubMed  Google Scholar 

  7. Pivarcsi A, Bodai L, Rethi B, et al. Expression and function of toll-like receptors 2 and 4 in human keratinocytes. Int Immunol 2003; 15 (6): 721–30

    CAS  PubMed  Google Scholar 

  8. Renn CN, Sanchez DJ, Ochoa MT, et al. TLR activation of Langerhans cell-like dendritic cells triggers an antiviral immune response. J Immunol 2006; 177 (1): 298–305

    CAS  PubMed  Google Scholar 

  9. Voelcker V, Gebhardt C, Averbeck M, et al. Hyaluronan fragments induce cytokine and metalloprotease upregulation in humanmelanoma cells in part by signalling via TLR4. Exp Dermatol 2008; 17 (2): 100–7

    CAS  PubMed  Google Scholar 

  10. Harwani SC, Lurain NS, Zariffard MR, et al. Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferonbeta in human foreskin fibroblasts and cervical tissue. Virol J 2007; 4: 133

    PubMed Central  PubMed  Google Scholar 

  11. Rozis G, Benlahrech A, Duraisingham S, et al. Human Langerhans’ cells and dermal-type dendritic cells generated from CD34 stem cells express different toll-like receptors and secrete different cytokines in response to toll-like receptor ligands. Immunology 2008; 124 (3): 329–38

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Flacher V, Bouschbacher M, Verronese E, et al. Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria. J Immunol 2006; 177 (11): 7959–67

    CAS  PubMed  Google Scholar 

  13. Kulka M, Alexopoulou L, Flavell RA, et al. Activation of mast cells by double-stranded RNA: evidence for activation through toll-like receptor 3. J Allergy Clin Immunol 2004; 114 (1): 174–82

    CAS  PubMed  Google Scholar 

  14. Kawai T, Akira S. Pathogen recognition with toll-like receptors. Curr Opin Immunol 2005; 17 (4): 338–44

    CAS  PubMed  Google Scholar 

  15. Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 2000; 1 (5): 398–401

    CAS  PubMed  Google Scholar 

  16. Beg AA. Endogenous ligands of toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002; 23 (11): 509–12

    CAS  PubMed  Google Scholar 

  17. Biragyn A, Ruffini PA, Leifer CA, et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 2002; 298 (5595): 1025–9

    CAS  PubMed  Google Scholar 

  18. Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates toll-like receptor 4. J Biol Chem 2001; 276 (13): 10229–33

    CAS  PubMed  Google Scholar 

  19. Schwandner R, Dziarski R, Wesche H, et al. Peptidoglycan–and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 1999; 274 (25): 17406–9

    CAS  PubMed  Google Scholar 

  20. Gilleron M, Quesniaux VF, Puzo G. Acylation state of the phosphatidylinositol hexamannosides from Mycobacterium bovis bacillus Calmette Guerin and Mycobacterium tuberculosis H37Rv and its implication in toll-like receptor response. J Biol Chem 2003; 278 (32): 29880–9

    CAS  PubMed  Google Scholar 

  21. Bieback K, Lien E, Klagge IM, et al. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 2002; 76 (17): 8729–36

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Hawn TR, Misch EA, Dunstan SJ, et al. A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur J Immunol 2007; 37 (8): 2280–9

    CAS  PubMed  Google Scholar 

  23. Lopez M, Sly LM, Luu Y, et al. The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through toll-like receptor-2. J Immunol 2003; 170 (5): 2409–16

    CAS  PubMed  Google Scholar 

  24. Hajjar AM, O’Mahony DS, Ozinsky A, et al. Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J Immunol 2001; 166 (1): 15–9

    CAS  PubMed  Google Scholar 

  25. Sato M, Sano H, Iwaki D, et al. Direct binding of toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. J Immunol 2003; 171 (1): 417–25

    CAS  PubMed  Google Scholar 

  26. Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature 2001; 410 (6832): 1099–103

    CAS  PubMed  Google Scholar 

  27. Mizel SB, Honko AN, Moors MA, et al. Induction ofmacrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric toll-like receptor 5/toll-like receptor 4 complexes. J Immunol 2003; 170 (12): 6217–23

    CAS  PubMed  Google Scholar 

  28. Wagner H. The immunobiology of the TLR9 subfamily. Trends Immunol 2004; 25 (7): 381–6

    CAS  PubMed  Google Scholar 

  29. Alexopoulou L, Holt AC, Medzhitov R, et al. Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature 2001; 413 (6857): 732–8

    CAS  PubMed  Google Scholar 

  30. Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002; 3 (2): 196–200

    CAS  PubMed  Google Scholar 

  31. Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303 (5663): 1526–9

    CAS  PubMed  Google Scholar 

  32. Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004; 303 (5663): 1529–31

    CAS  PubMed  Google Scholar 

  33. Hemmi H, Takeuchi O, Kawai T, et al. A toll-like receptor recognizes bacterial DNA. Nature 2000; 408 (6813): 740–5

    CAS  PubMed  Google Scholar 

  34. Hasan U, Chaffois C, Gaillard C, et al. Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 2005; 174 (5): 2942–50

    CAS  PubMed  Google Scholar 

  35. Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 1988; 52 (2): 269–79

    CAS  PubMed  Google Scholar 

  36. Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301 (5633): 640–3

    CAS  PubMed  Google Scholar 

  37. Fitzgerald KA, Rowe DC, Barnes BJ, et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 2003; 198 (7): 1043–55

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Fitzgerald KA, McWhirter SM, Faia KL, et al. IK Kepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003; 4 (5): 491–6

    CAS  PubMed  Google Scholar 

  39. Blander JM, Medzhitov R. Regulation of phagosome maturation by signals from toll-like receptors. Science 2004; 304 (5673): 1014–8

    CAS  PubMed  Google Scholar 

  40. Underhill DM, Ozinsky A, Hajjar AM, et al. The toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 1999; 401 (6755): 811–5

    CAS  PubMed  Google Scholar 

  41. Tsuji S, Matsumoto M, Takeuchi O, et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of toll-like receptors. Infect Immun 2000; 68 (12): 6883–90

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Michelsen KS, Aicher A, Mohaupt M, et al. The role of toll-like receptors (TLRs) in bacteria-induced maturation of murine dendritic cells (DCS): peptidoglycan and lipoteichoic acid are inducers of DC maturation and require TLR2. J Biol Chem 2001; 276 (28): 25680–6

    CAS  PubMed  Google Scholar 

  43. Heit A, Maurer T, Hochrein H, et al. Cutting edge: Toll-like receptor 9 expression is not required for CpG DNA-aided cross-presentation of DNA conjugated antigens but essential for cross-priming of CD8 T cells. J Immunol 2003; 170 (6): 2802–5

    CAS  PubMed  Google Scholar 

  44. Zaks K, Jordan M, Guth A, et al. Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes. J Immunol 2006; 176 (12): 7335–45

    CAS  PubMed  Google Scholar 

  45. Becker MN, Diamond G, Verghese MW, et al. CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J Biol Chem 2000; 275 (38): 29731–6

    CAS  PubMed  Google Scholar 

  46. Hertz CJ, Wu Q, Porter EM, et al. Activation of toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. J Immunol 2003; 171 (12): 6820–6

    CAS  PubMed  Google Scholar 

  47. Bolz DD, Sundsbak RS, Ma Y, et al. MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J Immunol 2004; 173 (3): 2003–10

    CAS  PubMed  Google Scholar 

  48. Loof TG, Goldmann O, Medina E. Immune recognition of Streptococcus pyogenes by dendritic cells. Infect Immun 2008; 76 (6): 2785–92

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Morrison LA. The toll of herpes simplex virus infection. Trends Microbiol 2004; 12 (8): 353–6

    CAS  PubMed  Google Scholar 

  50. Sato A, Linehan MM, Iwasaki A. Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci U S A 2006; 103 (46): 17343–8

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Stack J, Haga IR, Schröder M, et al. Vaccinia virus protein A46R targets multiple toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 2005; 201: 1007–18

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Roeder A, Kirschning CJ, Rupec RA, et al. Toll-like receptors as key mediators in innate antifungal immunity. Med Mycol 2004; 42 (6): 485–98

    CAS  PubMed  Google Scholar 

  53. Weindl G, Naglik JR, Kaesler S, et al. Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling. J Clin Invest 2007; 117 (12): 3664–72

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Dabbagh K, Lewis DB. Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 2003; 16 (3): 199–204

    PubMed  Google Scholar 

  55. Into T, Kiura K, Yasuda M, et al. Stimulation of human toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Cell Microbiol 2004; 6 (2): 187–99

    CAS  PubMed  Google Scholar 

  56. Yamamura M, Uyemura K, Deans RJ, et al. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 1991; 254 (5029): 277–9

    CAS  PubMed  Google Scholar 

  57. Krutzik SR, Modlin RL. The role of toll-like receptors in combating mycobacteria. Semin Immunol 2004; 16 (1): 35–41

    CAS  PubMed  Google Scholar 

  58. Krutzik SR, Ochoa MT, Sieling PA, et al. Activation and regulation of toll-like receptors 2 and 1 in human leprosy. Nat Med 2003; 9 (5): 525–32

    CAS  PubMed  Google Scholar 

  59. McInturff JE, Modlin RL, Kim J. The role of toll-like receptors in the pathogenesis and treatment of dermatological disease. J Invest Dermatol 2005; 125 (1): 1–8

    CAS  PubMed  Google Scholar 

  60. Bochud PY, Hawn TR, Siddiqui MR, et al. Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 2008; 197 (2): 253–61

    CAS  PubMed  Google Scholar 

  61. Johnson CM, Lyle EA, Omueti KO, et al. Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 2007; 178 (12): 7520–4

    CAS  PubMed  Google Scholar 

  62. Misch EA, Macdonald M, Ranjit C, et al. Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2008; 2 (5): e231

    Google Scholar 

  63. Oliveira RB, Ochoa MT, Sieling PA, et al. Expression of toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect Immun 2003; 71 (3): 1427–33

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Vowels BR, Yang S, Leyden JJ. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne. Infect Immun 1995; 63 (8): 3158–65

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Kim J, Ochoa MT, Krutzik SR, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169 (3): 1535–41

    CAS  PubMed  Google Scholar 

  66. Jugeau S, Tenaud I, Knol AC, et al. Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol 2005; 153 (6): 1105–13

    CAS  PubMed  Google Scholar 

  67. Shibata M, Katsuyama M, Onodera T, et al. Glucocorticoids enhance toll-like receptor 2 expression in human keratinocytes stimulated with propionibacterium acnes or proinflammatory cytokines. J Invest Dermatol 2009; 129 (2): 375–82

    CAS  PubMed  Google Scholar 

  68. Tenaud I, Khammari A, Dreno B. In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inflammatory lesions. Exp Dermatol 2007; 16 (6): 500–6

    CAS  PubMed  Google Scholar 

  69. Liu PT, Krutzik SR, Kim J, et al. Cutting edge: all-trans retinoic acid down-regulates TLR2 expression and function. J Immunol 2005; 174 (5): 2467–70

    CAS  PubMed  Google Scholar 

  70. Hasannejad H, Takahashi R, Kimishima M, et al. Selective impairment of toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol 2007; 120 (1): 69–75

    CAS  PubMed  Google Scholar 

  71. Mrabet-Dahbi S, Dalpke AH, Niebuhr M, et al. The toll-like receptor 2 R753Q mutation modifies cytokine production and toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 2008; 121 (4): 1013–9

    CAS  PubMed  Google Scholar 

  72. Niebuhr M, Langnickel J, Draing C, et al. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patientswith atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy 2008; 63 (6): 728–34

    CAS  PubMed  Google Scholar 

  73. Weidinger S, Novak N, Klopp N, et al. Lack of association between toll-like receptor 2 and toll-like receptor 4 polymorphisms and atopic eczema. J Allergy Clin Immunol 2006; 118 (1): 277–9

    CAS  PubMed  Google Scholar 

  74. Novak N, Yu CF, Bussmann C, et al. Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007; 62 (7): 766–72

    CAS  PubMed  Google Scholar 

  75. Lauener RP, Birchler T, Adamski J, et al. Expression of CD14 and toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 2002; 360 (9331): 465–6

    CAS  PubMed  Google Scholar 

  76. Ding C, Wang L, Al-Ghawi H, et al. toll-like receptor engagement stimulates anti-snRNP autoreactive B cells for activation. Eur J Immunol 2006; 36 (8): 2013–24

    CAS  PubMed  Google Scholar 

  77. Ehlers M, Fukuyama H, McGaha TL, et al. TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. J Exp Med 2006; 203 (3): 553–61

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Lau CM, Broughton C, Tabor AS, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/toll-like receptor 7 engagement. J Exp Med 2005; 202 (9): 1171–7

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Barrat FJ, Meeker T, Gregorio J, et al. Nucleic acids of mammalian origin can act as endogenous ligands for toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 2005; 202 (8): 1131–9

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Boule MW, Broughton C, Mackay F, et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med 2004; 199 (12): 1631–40

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Savarese E, Chae OW, Trowitzsch S, et al. U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 2006; 107 (8): 3229–34

    CAS  PubMed  Google Scholar 

  82. Tao K, Fujii M, Tsukumo S, et al. Genetic variations of toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis 2007; 66 (7): 905–9

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Xu CJ, Zhang WH, Pan HF, et al. Association study of a single nucleotide polymorphism in the exon 2 region of toll-like receptor 9 (TLR9) gene with susceptibility to systemic lupus erythematosus among Chinese. Mol Biol Rep. 2009; 36 (8): 2245–8

    CAS  PubMed  Google Scholar 

  84. Herlands RA, Christensen SR, Sweet RA, et al. Cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity 2008; 29 (2): 249–60

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 2007; 8 (5): 487–96

    CAS  PubMed  Google Scholar 

  86. Rahman AH, Eisenberg RA. The role of toll-like receptors in systemic lupus erythematosus. Springer Semin Immunopathol 2006; 28 (2): 131–43

    CAS  PubMed  Google Scholar 

  87. Yoshizaki A, Iwata Y, Komura K, et al. CD19 regulates skin and lung fibrosis via toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol 2008; 172 (6): 1650–63

    PubMed Central  CAS  PubMed  Google Scholar 

  88. 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 (4): 670–9

    CAS  PubMed  Google Scholar 

  89. Begon E, Michel L, Flageul B, et al. Expression, subcellular localization and cytokinic modulation of toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin. Eur J Dermatol 2007; 17 (6): 497–506

    CAS  PubMed  Google Scholar 

  90. Candia L, Marquez J, Hernandez C, et al. Toll-like receptor-2 expression is upregulated in antigen-presenting cells from patients with psoriatic arthritis: a pathogenic role for innate immunity? J Rheumatol 2007; 34 (2): 374–9

    CAS  PubMed  Google Scholar 

  91. Seung NR, Park EJ, Kim CW, et al. Comparison of expression of heat-shock protein 60, toll-like receptors 2 and 4, and T-cell receptor gammadelta in plaque and guttate psoriasis. J Cutan Pathol 2007; 34 (12): 903–11

    PubMed  Google Scholar 

  92. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347 (15): 1151–60

    CAS  PubMed  Google Scholar 

  93. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449 (7162): 564–9

    CAS  PubMed  Google Scholar 

  94. Alexopoulou L, Thomas V, Schnare M, et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2- deficient mice. Nat Med 2002; 8 (8): 878–84

    CAS  PubMed  Google Scholar 

  95. Salazar JC, Pope CD, Sellati TJ, et al. Coevolution of markers of innate and adaptive immunity in skin and peripheral blood of patients with erythema migrans. J Immunol 2003; 171 (5): 2660–70

    CAS  PubMed  Google Scholar 

  96. Schroder NW, Heine H, Alexander C, et al. Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. J Immunol 2004; 173 (4): 2683–91

    PubMed  Google Scholar 

  97. Schroder NW, Eckert J, Stubs G, et al. Immune responses induced by spirochetal outer membrane lipoproteins and glycolipids. Immunobiology 2008; 213 (3-4): 329–40

    PubMed  Google Scholar 

  98. Cabral ES, Gelderblom H, Hornung RL, et al. Borrelia burgdorferi lipoprotein-mediated TLR2 stimulation causes the down-regulation of TLR5 in human monocytes. J Infect Dis 2006; 193 (6): 849–59

    CAS  PubMed  Google Scholar 

  99. Behera AK, Hildebrand E, Bronson RT, et al. MyD88 deficiency results in tissue-specific changes in cytokine induction and inflammation in interleukin-18-independent mice infected with Borrelia burgdorferi. Infect Immun 2006; 74 (3): 1462–70

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Bouis DA, Popova TG, Takashima A, et al. Dendritic cells phagocytose and are activated by Treponema pallidum. Infect Immun 2001; 69 (1): 518–28

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Mothes N, Heinzkill M, Drachenberg KJ, et al. Allergen-specific immunotherapy with a monophosphoryl lipid A-adjuvanted vaccine: reduced seasonally boosted immunoglobulin E production and inhibition of basophil histamine release by therapy-induced blocking antibodies. Clin Exp Allergy 2003; 33 (9): 1198–208

    CAS  PubMed  Google Scholar 

  102. Creticos PS, Schroeder JT, Hamilton RG, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 2006; 355 (14): 1445–55

    CAS  PubMed  Google Scholar 

  103. Schon MP, Schon M. Immunemodulation and apoptosis induction: two sides of the antitumoral activity of imiquimod. Apoptosis 2004; 9 (3): 291–8

    CAS  PubMed  Google Scholar 

  104. Kodner CM, Nasraty S. Management of genital warts. Am Fam Physician 2004; 70 (12): 2335–42

    PubMed  Google Scholar 

  105. Wille-Reece U, Flynn BJ, Lore K, et al. HIV Gag protein conjugated to a toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci U S A 2005; 102 (42): 15190–4

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Kalali BN, Kollisch G, Mages J, et al. Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-,and MDA5/RIG-I-mediated differential signaling. J Immunol 2008; 181 (4): 2694–704

    CAS  PubMed  Google Scholar 

  107. Schon MP, Schon M, Klotz KN. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7-and TLR8-independent fashion. J Invest Dermatol 2006; 126 (6): 1338–47

    PubMed  Google Scholar 

  108. Stary G, Bangert C, Tauber M, et al. Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J Exp Med 2007; 204 (6): 1441–51

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Clark RA, Huang SJ, Murphy GF, et al. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 2008; 205 (10): 2221–34

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Gill N, Davies EJ, Ashkar AA. The role of toll-like receptor ligands/agonists in protection against genital HSV-2 infection. Am J Reprod Immunol 2008; 59 (1): 35–43

    CAS  PubMed  Google Scholar 

  111. Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunotherapy for melanoma. J Clin Oncol 2008; 26 (20): 3445–55

    CAS  PubMed  Google Scholar 

  112. Dummer R, Hauschild A, Becker JC, et al. An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin Cancer Res 2008; 14 (3): 856–64

    CAS  PubMed  Google Scholar 

  113. Tse K, Horner AA. Update on toll-like receptor-directed therapies for human disease. Ann Rheum Dis 2007; 66 Suppl. 3: iii 77–80

    Google Scholar 

  114. Adams S, O’Neill DW, Nonaka D, et al. Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J Immunol 2008; 181 (1): 776–84

    CAS  PubMed  Google Scholar 

  115. Wysocka M, Benoit BM, Newton S, et al. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15. Blood 2004; 104 (13): 4142–9

    CAS  PubMed  Google Scholar 

  116. Wysocka M, Newton S, Benoit BM, et al. Synthetic imidazoquinolines potently and broadly activate the cellular immune response of patients with cutaneous T-cell lymphoma: synergy with interferon-gamma enhances production of interleukin-12. Clin Lymphoma Myeloma 2007; 7 (8): 524–34

    CAS  PubMed  Google Scholar 

  117. Hwang ST, Janik JE, Jaffe ES, et al. Mycosis fungoides and Sezary syndrome. Lancet 2008; 371 (9616): 945–57

    CAS  PubMed  Google Scholar 

  118. Yu P, Musette P, Peng SL. Toll-like receptor 9 in murine lupus: more friend than foe! Immunobiology 2008; 213 (2): 151–7

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Dermatology and Allergy, Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Dorothea Terhorst

  2. Department of Dermatology and Allergy, Biederstein, Technische Universität München, Munich, Germany

    Behnam Naderi Kalali, Markus Ollert, Johannes Ring &  Martin Mempel

  3. Clinical Research Division of Molecular and Clinical Allergotoxicology, Technische Universität München, Munich, Germany

    Behnam Naderi Kalali, Markus Ollert &  Martin Mempel

  4. Division of Environmental Dermatology and Allergy, Helmholtz Center Munich/Technische Universität München, Biedersteiner Str. 29, D-80802, Munich, Germany

    Johannes Ring &  Martin Mempel

Authors
  1. Dorothea Terhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Behnam Naderi Kalali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Ollert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johannes Ring
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin Mempel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Mempel.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Terhorst, D., Kalali, B.N., Ollert, M. et al. The Role of Toll-Like Receptors in Host Defenses and Their Relevance to Dermatologic Diseases. AM J Clin Dermatol 11, 1–10 (2010). https://doi.org/10.2165/11311110-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11311110-000000000-00000

Keywords

  • Psoriasis
  • Acne
  • Leprosy
  • Lyme Disease
  • Imiquimod