Schmidt M, Raghavan B, Muller V et al.Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11:814-819

Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Nature Immunology (Impact Factor: 20). 09/2010; 11(9):814-9. DOI: 10.1038/ni.1919
Source: PubMed


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.

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Available from: Badrinarayanan Raghavan
    • "TLR3, 4, 5 and 9 (Flacher et al., 2006; Lebre et al., 2007; Olaru and Jensen, 2010) whereas other data suggest only substantial expression of TLR3 (Kollisch et al., 2005; Oosterhoff et al., 2013). After the discovery that nickel and cobalt metal ions could associate with TLR4 thus activating downstream signaling (Schmidt et al., 2010), we recently reported that palladium ions show the same capacity (Rachmawati et al., 2013). Subsequently we found that gold-ions could trigger TLR3, whereas mercury and copper also activated IL-8 release, the latter metal potentially via TLR5 (Rachmawati et al., 2015). "
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    ABSTRACT: Gold, nickel, copper and mercury, i.e. four metals frequently used in dental applications, were explored for their capacity to induce innate immune activation in keratinocytes (KC). Due to their anatomical location the latter epithelial cells are key in primary local irritative responses of skin and mucosa. Fresh foreskin-derived keratinocytes and skin and gingiva KC cell lines were studied for IL-8 release as a most sensitive parameter for NF-kB activation. First, we verified that viral-defense mediating TLR3 is a key innate immune receptor in both skin- and mucosa derived keratinocytes. Second, we found that, in line with our earlier finding that ionized gold can mimic viral dsRNA in triggering TLR3, gold is very effective in KC activation. It would appear that epithelial TLR3 can play a key role in both skin- and mucosa localized irritation reactivities to gold. Subsequently we found that not only gold, but also nickel, copper and mercury salts can activate innate immune reactivity in keratinocytes, although the pathways involved remain unclear. Although current alloys have been optimized for minimal leakage of metal ions, secondary factors such as mechanical friction and acidity may still facilitate such leakage. Subsequently, these metal ions may create local irritation, itching and swelling by triggering innate immune reactions, potentially also facilitating the development of metal specific adaptive immunity.
    No preview · Article · Oct 2015 · Toxicology in Vitro
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    • "Although this study provided valuable information on gene expression changes in the elicitation phase of allergic contact dermatitis, it cannot be used to confirm the HaCaT gene signature, as this signature presents part of the sensitization phase. In addition, the mechanisms underlying nickel sensitization are different from other sensitizing chemicals, as sensitization to nickel does not require covalent binding to proteins (Schmidt et al., 2010). The study presented here is aimed to provide a foundation for the human relevance of the HaCaT gene signature. "
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    ABSTRACT: The skin sensitizing potential of chemicals is mainly assessed using animal methods, such as the murine local lymph node assay. Recently, an in vitro assay based ona gene expression signaturein the HaCaT keratinocytecell linewas proposedas an alternative to these animal methods. Here, the human relevance of this gene signature is assessed through exposure of freshly isolated human skin to the chemical allergens dinitrochlorobenzene (DNCB) and diphenylcyclopropenone (DCP). In human skin, the gene signature shows similar direction of regulation as was previously observed in vitro, suggesting that the molecular processes that drive expression of these genes are similar between the HaCaT cell line and freshly isolated skin, providing evidence for the human relevance of the gene signature.
    Full-text · Article · Sep 2014 · Toxicology in Vitro
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    • "LPS stimulates innate immunity via Toll-like receptor 4 (TLR4), and TLRs may modify adaptive immunity [30]. Recently, Schmidt et al. reported that Ni directly stimulates human TLR4, but not mouse TLR4, which may be crucial for the development of contact allergy [31]. In this study, we identified the accumulation of T cells in the footpads of Cr plus LPS sensitized–Cr-challenged mice compared with those of Cr without LPS sensitized–Cr-challenged mice. "
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    ABSTRACT: Chromium (Cr) causes delayed-type hypersensitivity reactions possibly mediated by accumulating T cells into allergic inflamed skin, which are called irritants or allergic contact dermatitis. However, accumulating T cells during development of metal allergy are poorly characterized because a suitable animal model is not available. This study aimed to elucidate the skewing of T-cell receptor (TCR) repertoire and cytokine profiles in accumulated T cells in inflamed skin during elucidation of Cr allergy. A novel model of Cr allergy was induced by two sensitizations of Cr plus lipopolysaccharide solution into mouse groin followed by single Cr challenge into the footpad. TCR repertoires and nucleotide sequences of complementary determining region 3 were assessed in accumulated T cells from inflamed skin. Cytokine expression profiles and T-cell phenotypes were determined by qPCR. CD3+CD4+ T cells accumulated in allergic footpads and produced increased T helper 1 (Th1) type cytokines, Fas, and Fas ligand in the footpads after challenge, suggesting CD4+ Th1 cells locally expanded in response to Cr. Accumulated T cells included natural killer (NK) T cells and Cr-specific T cells with VA11-1/VB14-1 usage, suggesting metal-specific T cells driven by invariant NKT cells might contribute to the pathogenesis of Cr allergy.
    Full-text · Article · Jan 2014 · PLoS ONE
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