Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel.
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.
Schmidt
Marc
M
Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Raghavan
Badrinarayanan
B
Müller
Verena
V
Vogl
Thomas
T
Fejer
György
G
Tchaptchet
Sandrine
S
Keck
Simone
S
Kalis
Christoph
C
Nielsen
Peter J
PJ
Galanos
Chris
C
Roth
Johannes
J
Skerra
Arne
A
Martin
Stefan F
SF
Freudenberg
Marina A
MA
Goebeler
Matthias
M
D000595:Amino Acid Sequence; D000818:Animals; D003877:Dermatitis, Contact; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009532:Nickel / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
D011994:Recombinant Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009532:Nickel