Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2 |
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Authors: | Badrinarayanan Raghavan Stefan F Martin Philipp R Esser Matthias Goebeler Marc Schmidt |
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Affiliation: | 1. Department of Dermatology, University of Würzburg, , 97080 Würzburg;2. Department of Dermatology, University Medical Center Freiburg, , 79104 Freiburg, Germany |
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Abstract: | Development of contact allergy requires cooperation of adaptive and innate immunity. Ni2+ 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 Co2+ 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. |
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Keywords: | contact allergy dermatitis inflammation innate immunity Toll‐like receptor |
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