Innate Immune System Response in Metal Allergy: Toll-Like Receptors

  • Marc Schmidt
  • Matthias Goebeler


Sensitization is a prerequisite for the development of allergic contact dermatitis. Its initiation, however, is—as mistakenly assumed for quite a while—not just dependent on an adaptive immune response, but also requires a supplementary signal that activates the innate immune system. Many metal allergens are capable of delivering both signals—the mandatory antigenic stimulus and an innate proinflammatory signal. In recent years, the molecular mechanisms of metal-induced innate immune activation have at least in part been deciphered. It turned out that nickel, cobalt and presumably palladium directly bind to Toll-like receptor 4 (TLR4) in humans, resulting in receptor dimerization, activation and subsequent gene transcription. On the other hand, metal compounds may injure cells and tissue leading to alteration of extracellular matrix molecules such as hyaluronan, which can serve as endogenous ligands for TLRs. Additionally, metal haptens may induce reactive oxygen species (ROS) that result in activation of the inflammasome, a multimeric protein platform that controls release of the proinflammatory cytokines IL-1β and IL-18. A recently identified powerful activator of the inflammasome is the widespread contact hapten dichromate. Importantly, TLR and inflammasome activation may occur at the same time and collaborate in delivering innate immune signals. Finally, the coincident presence of microbial pathogens that can activate TLRs may support the development of contact allergies to metals. A better understanding of the mechanisms by which metal allergens are sensed by the innate immune system may contribute to the design of novel therapeutic approaches for this common allergic disease.


  1. 1.
    McKee AS, Fontenot AP. Interplay of innate and adaptive immunity in metal-induced hypersensitivity. Curr Opin Immunol. 2016;42:25–30. doi: 10.1016/j.coi.2016.05.001.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schmidt M, Goebeler M. Immunology of metal allergies. J Dtsch Dermatol Ges. 2015;13(7):653–60. doi: 10.1111/ddg.12673.CrossRefGoogle Scholar
  3. 3.
    Mahnke K, Ring S, Enk AH. Antibody targeting of “steady-state” dendritic cells induces tolerance mediated by regulatory T cells. Front Immunol. 2016;7:63. doi: 10.3389/fimmu.2016.00063.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kaplan DH, Igyarto BZ, Gaspari AA. Early immune events in the induction of allergic contact dermatitis. Nat Rev Immunol. 2012;12(2):114–24. doi: 10.1038/nri3150.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41(5):694–707. doi: 10.1016/j.immuni.2014.10.008.CrossRefPubMedGoogle Scholar
  6. 6.
    Staite ND, Justen JM, Sly LM, Beaudet AL, Bullard DC. Inhibition of delayed-type contact hypersensitivity in mice deficient in both E-selectin and P-selectin. Blood. 1996;88(8):2973–9.PubMedGoogle Scholar
  7. 7.
    Saito M, Arakaki R, Yamada A, Tsunematsu T, Kudo Y, Ishimaru N. Molecular mechanisms of nickel allergy. Int J Mol Sci. 2016;17(2). doi: 10.3390/ijms17020202.CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Schmidt M, Goebeler M. Nickel allergies: paying the Toll for innate immunity. J Mol Med (Berl). 2011;89(10):961–70. doi: 10.1007/s00109-011-0780-0.CrossRefGoogle Scholar
  9. 9.
    Sato N, Kinbara M, Kuroishi T, Kimura K, Iwakura Y, Ohtsu H, Sugawara S, Endo Y. Lipopolysaccharide promotes and augments metal allergies in mice, dependent on innate immunity and histidine decarboxylase. Clin Exp Allergy. 2007;37(5):743–51. doi: 10.1111/j.1365-2222.2007.02705.x.CrossRefPubMedGoogle Scholar
  10. 10.
    Goebeler M, Meinardus-Hager G, Roth J, Goerdt S, Sorg C. Nickel chloride and cobalt chloride, two common contact sensitizers, directly induce expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (ELAM-1) by endothelial cells. J Invest Dermatol. 1993;100(6):759–65.CrossRefGoogle Scholar
  11. 11.
    Goebeler M, Roth J, Brocker EB, Sorg C, Schulze-Osthoff K. Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt. J Immunol. 1995;155(5):2459–67.PubMedGoogle Scholar
  12. 12.
    Goebeler M, Trautmann A, Voss A, Brocker EV, Toksoy A, Gillitzer R. Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity. Am J Pathol. 2001;158(2):431–40.CrossRefGoogle Scholar
  13. 13.
    Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16(4):343–53. doi: 10.1038/ni.3123.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22(2):240–73. doi: 10.1128/CMR.00046-08.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Martin SF, Dudda JC, Bachtanian E, Lembo A, Liller S, Durr C, Heimesaat MM, Bereswill S, Fejer G, Vassileva R, Jakob T, Freudenberg N, Termeer CC, Johner C, Galanos C, Freudenberg MA. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med. 2008;205(9):2151–62. doi: 10.1084/jem.20070509.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, Thorne PS, Wills-Karp M, Gioannini TL, Weiss JP, Karp CL. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009;457(7229):585–8. doi: 10.1038/nature07548.CrossRefPubMedGoogle Scholar
  17. 17.
    Herre J, Gronlund H, Brooks H, Hopkins L, Waggoner L, Murton B, Gangloff M, Opaleye O, Chilvers ER, Fitzgerald K, Gay N, Monie T, Bryant C. Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands. J Immunol. 2013;191(4):1529–35. doi: 10.4049/jimmunol.1300284.CrossRefPubMedGoogle Scholar
  18. 18.
    Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–84. doi: 10.1038/ni.1863.CrossRefGoogle Scholar
  19. 19.
    Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–9. doi: 10.1038/nm1315.CrossRefPubMedGoogle Scholar
  20. 20.
    Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002;277(17):15028–34. doi: 10.1074/jbc.M200497200.CrossRefPubMedGoogle Scholar
  21. 21.
    Loser K, Vogl T, Voskort M, Lueken A, Kupas V, Nacken W, Klenner L, Kuhn A, Foell D, Sorokin L, Luger TA, Roth J, Beissert S. The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med. 2010;16(6):713–7. doi: 10.1038/nm.2150.CrossRefPubMedGoogle Scholar
  22. 22.
    Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M, Malle E, Schaefer RM, Grone HJ. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest. 2005;115(8):2223–33. doi: 10.1172/JCI23755.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Viemann D, Schmidt M, Tenbrock K, Schmid S, Muller V, Klimmek K, Ludwig S, Roth J, Goebeler M. The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007;178(5):3198–207.CrossRefGoogle Scholar
  24. 24.
    Schmidt M, Raghavan B, Muller V, Vogl T, Fejer G, Tchaptchet S, Keck S, Kalis C, Nielsen PJ, Galanos C, Roth J, Skerra A, Martin SF, Freudenberg MA, Goebeler M. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol. 2010;11(9):814–9. doi: 10.1038/ni.1919.CrossRefPubMedGoogle Scholar
  25. 25.
    Muller V, Viemann D, Schmidt M, Endres N, Ludwig S, Leverkus M, Roth J, Goebeler M. Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. J Immunol. 2007;179(12):8435–45.CrossRefGoogle Scholar
  26. 26.
    Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002;169(12):6668–72.CrossRefGoogle Scholar
  27. 27.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282(5396):2085–8.CrossRefGoogle Scholar
  28. 28.
    Raghavan B, Martin SF, Esser PR, Goebeler M, Schmidt M. Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2. EMBO Rep. 2012;13(12):1109–15. doi: 10.1038/embor.2012.155.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zoroddu MA, Peana M, Medici S, Potocki S, Kozlowski H. Ni(II) binding to the 429-460 peptide fragment from human Toll like receptor (hTLR4): a crucial role for nickel-induced contact allergy? Dalton Trans. 2014;43(7):2764–71. doi: 10.1039/c3dt52187g.CrossRefPubMedGoogle Scholar
  30. 30.
    Oblak A, Pohar J, Jerala R. MD-2 determinants of nickel and cobalt-mediated activation of human TLR4. PLoS One. 2015;10(3):e0120583. doi: 10.1371/journal.pone.0120583.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lawrence H, Mawdesley AE, Holland JP, Kirby JA, Deehan DJ, Tyson-Capper AJ. Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation. Oncotarget. 2016;7(7):7578–85. doi: 10.18632/oncotarget.7105.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Potnis PA, Dutta DK, Wood SC. Toll-like receptor 4 signaling pathway mediates proinflammatory immune response to cobalt-alloy particles. Cell Immunol. 2013;282(1):53–65. doi: 10.1016/j.cellimm.2013.04.003.CrossRefPubMedGoogle Scholar
  33. 33.
    Tyson-Capper AJ, Lawrence H, Holland JP, Deehan DJ, Kirby JA. Metal-on-metal hips: cobalt can induce an endotoxin-like response. Ann Rheum Dis. 2013;72(3):460–1. doi: 10.1136/annrheumdis-2012-202468.CrossRefPubMedGoogle Scholar
  34. 34.
    Rachmawati D, Bontkes HJ, Verstege MI, Muris J, von Blomberg BM, Scheper RJ, van Hoogstraten IM. Transition metal sensing by Toll-like receptor-4: next to nickel, cobalt and palladium are potent human dendritic cell stimulators. Contact Dermatitis. 2013;68(6):331–8. doi: 10.1111/cod.12042.CrossRefPubMedGoogle Scholar
  35. 35.
    Nakamura N, Tamagawa-Mineoka R, Ueta M, Kinoshita S, Katoh N. Toll-like receptor 3 increases allergic and irritant contact dermatitis. J Invest Dermatol. 2015;135(2):411–7. doi: 10.1038/jid.2014.402.CrossRefPubMedGoogle Scholar
  36. 36.
    Rachmawati D, Alsalem IW, Bontkes HJ, Verstege MI, Gibbs S, von Blomberg BM, Scheper RJ, van Hoogstraten IM. Innate stimulatory capacity of high molecular weight transition metals Au (gold) and Hg (mercury). Toxicol In Vitro. 2015;29(2):363–9. doi: 10.1016/j.tiv.2014.10.010.CrossRefPubMedGoogle Scholar
  37. 37.
    Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008;205(11):2609–21. doi: 10.1084/jem.20081370.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    He Y, Hara H, Nunez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012–21. doi: 10.1016/j.tibs.2016.09.002.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Honda T, Egawa G, Grabbe S, Kabashima K. Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J Invest Dermatol. 2013;133(2):303–15. doi: 10.1038/jid.2012.284.CrossRefPubMedGoogle Scholar
  40. 40.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787–91. doi: 10.4049/jimmunol.0901363.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287(43):36617–22. doi: 10.1074/jbc.M112.407130.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Adam C, Wohlfarth J, Haußmann M, Sennefelder H, Rodin A, Maler M, Martin SF, Goebeler M, Schmidt M. Allergy-inducing chromium compounds trigger potent innate immune stimulation via ROS-dependent inflammasome activation. J Invest Dermatol. 2016;137(2):367–76. doi: 10.1016/j.jid.2016.10.003.CrossRefPubMedGoogle Scholar
  43. 43.
    Dowling JK, Dellacasagrande J. Toll-like receptors: ligands, cell-based models, and readouts for receptor action. Methods Mol Biol. 2016;1390:3–27. doi: 10.1007/978-1-4939-3335-8_1.CrossRefPubMedGoogle Scholar
  44. 44.
    Hansen MB, Johansen JD, Menne T. Chromium allergy: significance of both Cr(III) and Cr(VI). Contact Dermatitis. 2003;49(4):206–12.CrossRefGoogle Scholar
  45. 45.
    Iyer VJ, Banerjee G, Govindram CB, Kamath V, Shinde S, Gaikwad A, Jerajani HR, Raman G, Cherian KM. Role of different valence states of chromium in the elicitation of allergic contact dermatitis. Contact Dermatitis. 2002;47(6):357–60.CrossRefGoogle Scholar
  46. 46.
    Nethercott J, Paustenbach D, Adams R, Fowler J, Marks J, Morton C, Taylor J, Horowitz S, Finley B. A study of chromium induced allergic contact dermatitis with 54 volunteers: implications for environmental risk assessment. Occup Environ Med. 1994;51(6):371–80.CrossRefGoogle Scholar
  47. 47.
    Takahashi H, Kinbara M, Sato N, Sasaki K, Sugawara S, Endo Y. Nickel allergy-promoting effects of microbial or inflammatory substances at the sensitization step in mice. Int Immunopharmacol. 2011;11(10):1534–40. doi: 10.1016/j.intimp.2011.05.010.CrossRefPubMedGoogle Scholar
  48. 48.
    Bonefeld CM, Nielsen MM, Vennegaard MT, Johansen JD, Geisler C, Thyssen JP. Nickel acts as an adjuvant during cobalt sensitization. Exp Dermatol. 2015;24(3):229–31. doi: 10.1111/exd.12634.CrossRefPubMedGoogle Scholar
  49. 49.
    Martin SF, Esser PR, Weber FC, Jakob T, Freudenberg MA, Schmidt M, Goebeler M. Mechanisms of chemical-induced innate immunity in allergic contact dermatitis. Allergy. 2011;66(9):1152–63. doi: 10.1111/j.1398-9995.2011.02652.x.CrossRefGoogle Scholar
  50. 50.
    Li X, Zhong F. Nickel induces interleukin-1beta secretion via the NLRP3-ASC-caspase-1 pathway. Inflammation. 2014;37(2):457–66. doi: 10.1007/s10753-013-9759-z.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Samelko L, Landgraeber S, McAllister K, Jacobs J, Hallab NJ. Cobalt alloy implant debris induces inflammation and bone loss primarily through danger signaling, not TLR4 activation: implications for DAMP-ening implant related inflammation. PLoS One. 2016;11(7):e0160141. doi: 10.1371/journal.pone.0160141.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Vennegaard MT, Dyring-Andersen B, Skov L, Nielsen MM, Schmidt JD, Bzorek M, Poulsen SS, Thomsen AR, Woetmann A, Thyssen JP, Johansen JD, Odum N, Menne T, Geisler C, Bonefeld CM. Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent and interleukin-1-dependent pathway. Contact Dermatitis. 2014;71(4):224–32. doi: 10.1111/cod.12270.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of DermatologyUniversity Hospital WürzburgWürzburgGermany

Personalised recommendations