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


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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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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Authors and Affiliations



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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The authors declare no competing financial interests.

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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).

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