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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout






Similar content being viewed by others
References
Mattila, L. et al. Prevalence of nickel allergy among Finnish university students in 1995. Contact Dermatitis 44, 218–223 (2001).
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).
Nestle, F.O., Speidel, H. & Speidel, M.O. Metallurgy: high nickel release from 1- and 2-euro coins. Nature 419, 132 (2002).
Spiewak, R., Pietowska, J. & Curzytek, K. Nickel: a unique allergen—from molecular structure to European legislation. Expert Rev. Clin. Immunol. 3, 851–859 (2008).
Grabbe, S. & Schwarz, T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).
Martin, S.F. & Jakob, T. From innate to adaptive immune responses in contact hypersensitivity. Curr. Opin. Allergy Clin. Immunol. 8, 289–293 (2008).
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).
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).
Goebeler, M. et al. Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity. Am. J. Pathol. 158, 431–440 (2001).
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).
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
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).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
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).
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).
Park, B.S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191–1195 (2009).
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).
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).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
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).
Martin, S.F. et al. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J. Exp. Med. 205, 2151–2162 (2008).
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).
Harding, M.M. The architecture of metal coordination groups in proteins. Acta Crystallogr. D Biol. Crystallogr. 60, 849–859 (2004).
Trompette, A. et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585–588 (2009).
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).
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).
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).
Freudenberg, M.A., Keppler, D. & Galanos, C. Requirement for lipopolysaccharide-responsive macrophages in galactosamine-induced sensitization to endotoxin. Infect. Immun. 51, 891–895 (1986).
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).
Fejer, G. et al. Key role of splenic myeloid DCs in the IFN-αβ response to adenoviruses in vivo. PLoS Pathog. 4, e1000208 (2008).
Cao, Z., Henzel, W.J. & Gao, X. IRAK: a kinase associated with the interleukin-1 receptor. Science 271, 1128–1131 (1996).
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).
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).
Czymai, T. et al. FOXO3 modulates endothelial gene expression and function by classical and alternative mechanisms. J. Biol. Chem. 285, 10163–10178 (2010).
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).
DeLano, W.L. The PyMOL Molecular Graphics System (DeLano Scientific, 2002).
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.).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 (PDF 4058 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.1919
This article is cited by
-
Application of toxicology in silico methods for prediction of acute toxicity (LD50) for Novichoks
Archives of Toxicology (2023)
-
Management von Kontaktekzemen
Allergo Journal (2023)
-
Toward a Molecular Diagnosis: Looking Under the Skin at Allergic Contact Dermatitis
Current Dermatology Reports (2023)
-
Orchestration of inflammation in contact allergy by innate immune and cellular stress responses
Allergo Journal International (2023)
-
Management of contact dermatitis
Allergo Journal International (2023)