Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2.
Development of contact allergy requires cooperation of adaptive and innate immunity. Ni(2+) stimulates innate immunity via TLR4/MD2, the bacterial LPS receptor. This likely involves receptor dimerization, but direct proof is pending and it is unclear if related haptens share this mechanism. We reveal Co(2+) as second metal stimulating TLR4 and confirm necessity of H456/H458 therein. Experiments with a new TLR4 dimerization mutant established dimerization as a mechanism of metal- and LPS-induced TLR4 activation. Yet, in interaction studies only LPS- but not metal-induced dimerization required MD2. Consistently, soluble TLR4 expressed without MD2 inhibited metal- but not LPS-induced responses, opening new therapeutic perspectives.
Department of Dermatology, University of Würzburg, Josef-Schneider Straße 2, 97080 Würzburg.
Badrinarayanan
B
Raghavan
Stefan F
SF
Martin
Philipp R
PR
Esser
Matthias
M
Goebeler
Marc
M
Schmidt
D056704:Adaptive Immunity / Q000235:genetics; D000485:Allergens / Q000633:toxicity; D000818:Animals; D003035:Cobalt / Q000633:toxicity*; D017449:Dermatitis, Allergic Contact / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D055503:Protein Multimerization; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000485:Allergens; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D050505:Mutant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003035:Cobalt; D009532:Nickel