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

Marc Schmidt, Badrinarayanan Raghavan, Verena Müller, Thomas Vogl, György Fejer, Sandrine Tchaptchet, Simone Keck, Christoph Kalis, Peter J. Nielsen, Chris Galanos, Johannes Roth, Arne Skerra, Stefan F. Martin, Marina A. Freudenberg, Matthias Goebeler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Allergies to nickel (Ni(2+)) 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 Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-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 Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni(2+) 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.
Original languageEnglish
Pages (from-to)814-819
Number of pages0
JournalNat Immunol
Volume11
Issue number9
DOIs
Publication statusPublished - Sept 2010

Keywords

  • Amino Acid Sequence
  • Animals
  • Dermatitis
  • Contact
  • Disease Models
  • Animal
  • Humans
  • Mice
  • Transgenic
  • Models
  • Molecular
  • Molecular Sequence Data
  • Nickel
  • Recombinant Proteins
  • Signal Transduction
  • Toll-Like Receptor 4

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