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.