Abstract

Recent findings unexpectedly revealed that human TLR4 can be directly activated by nickel ions. This activation is due to the coordination of nickel by a cluster of histidine residues on the ectodomain of human TLR4, which is absent in most other species. We aimed to elucidate the role of MD-2 in the molecular mechanism of TLR4/MD-2 activation by nickel, as nickel binding site on TLR4 is remote from MD-2, which directly binds the endotoxin as the main pathological activator of TLR4. We identified MD-2 and TLR4 mutants which abolished TLR4/MD-2 receptor activation by endotoxin but could nevertheless be significantly activated by nickel, which acts in synergy with LPS. Human TLR4/MD-2 was also activated by cobalt ions, while copper and cadmium were toxic in the tested concentration range. Activation of TLR4 by cobalt required MD-2 and was abolished by human TLR4 mutations of histidine residues at positions 456 and 458. We demonstrated that activation of TLR4 by nickel and cobalt ions can trigger both the MyD88-dependent and the –independent pathway. Based on our results we propose that predominantly hydrophobic interactions between MD-2 and TLR4 contribute to the stabilization of the TLR4/MD-2/metal ion complex in a conformation that enables activation.

Highlights

  • Allergic contact dermatitis (ACD) is one of the most common occupational skin diseases

  • Since the binding site for both metal ions seems to be completely distinct from the endotoxin binding site despite the apparent need for the presence of MD-2 in metal ion-induced activation, we focused on the possible interactions between TLR4 and MD-2 that might contribute to the receptor complex stabilization

  • We focused on MD-2 residues that contribute to the hydrophobic interactions that are indispensable for TLR4/MD-2 activation by endotoxin [6,7]

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Summary

Introduction

Allergic contact dermatitis (ACD) is one of the most common occupational skin diseases. Over 3000 contact allergens are known, with nickel being one of the most common ones. The prevalence of nickel hypersensitivity is 19,7–24,5% across Europe [2]. With such high prevalence measures have been taken to reduce the content of nickel in different alloys. ACD still remains a major problem since a range of everyday objects contains traces of allergenic metals, e. Cobalt is a trace element found in the body as the cofactor for vitamin B12, higher concentrations are highly toxic and can cause major health problems, including ACD [3]

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