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Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel

Abstract

Allergies to nickel (Ni2+) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni2+ triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni2+-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni2+ but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni2+ and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses.

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Figure 1: Activation of primary cells by the contact allergen Ni2+ requires MyD88–human TLR4.
Figure 2: Proinflammatory gene expression by Ni2+ requires human TLR4 and its co-receptor human MD2.
Figure 3: Ni2+-induced gene expression requires sequence motifs that are present in human TLR4 but not in mouse TLR4.
Figure 4: Non-conserved histidines in human TLR4 (hTLR4) provide a potential binding site for Ni2+.
Figure 5: Histidines H456 and H458 in human TLR4 (hTLR4) are required for Ni2+-induced proinflammatory gene expression.
Figure 6: Transgenic expression of human TLR4 in TLR4-deficient mice confers susceptibility to Ni2+ and allows induction of contact hypersensitivity.

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NCBI Reference Sequence

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References

  1. Mattila, L. et al. Prevalence of nickel allergy among Finnish university students in 1995. Contact Dermatitis 44, 218–223 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Liden, C., Skare, L. & Vahter, M. Release of nickel from coins and deposition onto skin from coin handling–comparing euro coins and SEK. Contact Dermatitis 59, 31–37 (2008).

    Article  PubMed  Google Scholar 

  3. Nestle, F.O., Speidel, H. & Speidel, M.O. Metallurgy: high nickel release from 1- and 2-euro coins. Nature 419, 132 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Spiewak, R., Pietowska, J. & Curzytek, K. Nickel: a unique allergen—from molecular structure to European legislation. Expert Rev. Clin. Immunol. 3, 851–859 (2008).

    Article  Google Scholar 

  5. Grabbe, S. & Schwarz, T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Martin, S.F. & Jakob, T. From innate to adaptive immune responses in contact hypersensitivity. Curr. Opin. Allergy Clin. Immunol. 8, 289–293 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Freudenberg, M.A., Esser, P.R., Jakob, T., Galanos, C. & Martin, S.F. Innate and adaptive immune responses in contact dermatitis: analogy with infections. G. Ital. Dermatol. Venereol. 144, 173–185 (2009).

    CAS  PubMed  Google Scholar 

  8. Goebeler, M., Roth, J., Bröcker, E.B., Sorg, C. & Schulze-Osthoff, K. Activation of nuclear factor-kB and gene expression in human endothelial cells by the common haptens nickel and cobalt. J. Immunol. 155, 2459–2467 (1995).

    CAS  PubMed  Google Scholar 

  9. Goebeler, M. et al. Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity. Am. J. Pathol. 158, 431–440 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Viemann, D. et al. The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-κB and hypoxia-inducible factor-1α. J. Immunol. 178, 3198–3207 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Eisenbarth, S.C., Colegio, O.R., O'Connor, W., Sutterwala, F.S. & Flavell, R.A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Wesche, H., Henzel, W.J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Hajjar, A.M., Ernst, R.K., Tsai, J.H., Wilson, C.B. & Miller, S.I. Human Toll-like receptor 4 recognizes host-specific LPS modifications. Nat. Immunol. 3, 354–359 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Park, B.S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191–1195 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Artik, S., von Vultèe, C., Gleichmann, E., Schwarz, T. & Griem, P. Nickel allergy in mice: enhanced sensitization capacity of nickel at higher oxidation states. J. Immunol. 163, 1143–1152 (1999).

    CAS  PubMed  Google Scholar 

  18. Sato, N. et al. Lipopolysaccharide promotes and augments metal allergies in mice, dependent on innate immunity and histidine decarboxylase. Clin. Exp. Allergy 37, 743–751 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Kalis, C. et al. Toll-like receptor 4 expression levels determine the degree of LPS-susceptibility in mice. Eur. J. Immunol. 33, 798–805 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Martin, S.F. et al. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J. Exp. Med. 205, 2151–2162 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ade, N. et al. NF-kappaB plays a major role in the maturation of human dendritic cells induced by NiSO(4) but not by DNCB. Toxicol. Sci. 99, 488–501 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Harding, M.M. The architecture of metal coordination groups in proteins. Acta Crystallogr. D Biol. Crystallogr. 60, 849–859 (2004).

    Article  PubMed  Google Scholar 

  24. Trompette, A. et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585–588 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Brinen, L.S., Willett, W.S., Craik, C.S. & Fletterick, R.J. X-ray structures of a designed binding site in trypsin show metal-dependent geometry. Biochemistry 35, 5999–6009 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Roth, J. et al. MRP8 and MRP14, S-100-like proteins associated with myeloid differentiation, are translocated to plasma membrane and intermediate filaments in a calcium-dependent manner. Blood 82, 1875–1883 (1993).

    CAS  PubMed  Google Scholar 

  27. Müller, V. et al. Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. J. Immunol. 179, 8435–8445 (2007).

    Article  PubMed  Google Scholar 

  28. Freudenberg, M.A., Keppler, D. & Galanos, C. Requirement for lipopolysaccharide-responsive macrophages in galactosamine-induced sensitization to endotoxin. Infect. Immun. 51, 891–895 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Vogl, T. et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat. Med. 13, 1042–1049 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Fejer, G. et al. Key role of splenic myeloid DCs in the IFN-αβ response to adenoviruses in vivo. PLoS Pathog. 4, e1000208 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cao, Z., Henzel, W.J. & Gao, X. IRAK: a kinase associated with the interleukin-1 receptor. Science 271, 1128–1131 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Muroi, M., Ohnishi, T. & Tanamoto, K. MD-2, a novel accessory molecule, is involved in species-specific actions of Salmonella lipid A. Infect. Immun. 70, 3546–3550 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Denk, A. et al. Activation of NF-κB via the IκB kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells. J. Biol. Chem. 276, 28451–28458 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Czymai, T. et al. FOXO3 modulates endothelial gene expression and function by classical and alternative mechanisms. J. Biol. Chem. 285, 10163–10178 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Poltorak, A. et al. Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis. 24, 340–355 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. DeLano, W.L. The PyMOL Molecular Graphics System (DeLano Scientific, 2002).

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Acknowledgements

We thank M. Muroi (National Institute of Health Sciences, Tokyo) for hMD2 and mMD2 expression constructs; A.M. Hajjar (Department of Immunology, University of Washington Medical School) for expression constructs for chimeric TLR4; A. Poltorak and B. Beutler (Scripps Research Institute, La Jolla, CA) for the BAC clone containing TLR4; B. Kanzler (Max-Planck-Institute for Immunobiology, Freiburg, Germany) for help in generating transgenic mice; and N. Schmidt, A. Huß, R. Alt, S. Sole, J. Ippisch and A. Meier for technical assistance. Supported by the Landesstiftung Baden-Württemberg (P-LS-AL2/07 to M.G. and M.S.), the Deutsche Forschungsgemeinschaft (GO 811/1-3 to M.G. and SPP 1110, project Fr 448/4 to M.A.F.) and the European Commission (LSHB-CT-2005-018681 to S.F.M.).

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Contributions

M.S., B.R., V.M., T.V., G.F., S.T., S.K., C.K., P.J.N., S.F.M. and M.A.F. performed the experiments. M.S., C.G., J.R., A.S., S.F.M., M.A.F. and M.G. designed the experiments and analyzed the data. M.G., M.S., S.F.M., A.S. and M.A.F. wrote the paper. M.G. managed the project and had overall responsibility for data interpretation and writing the manuscript. All authors discussed and commented on the manuscript.

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Correspondence to Matthias Goebeler.

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Schmidt, M., Raghavan, B., Müller, V. et al. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11, 814–819 (2010). https://doi.org/10.1038/ni.1919

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