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Nat Immunol. 2010 Sep;11(9):814-9. doi: 10.1038/ni.1919. Epub 2010 Aug 15.

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

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1
Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

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.

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PMID:
20711192
DOI:
10.1038/ni.1919
[Indexed for MEDLINE]

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