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    Ni TLR4 and CHS Paper

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    nickel allergy and importance of tlr3 receptors

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    © All Rights Reserved
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    Download as pdf or txt
    26 views2 pages

    Ni TLR4 and CHS Paper

    Uploaded by

    Vivek Goud
    nickel allergy and importance of tlr3 receptors

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    © All Rights Reserved
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    2010 Nature America, Inc. All rights reserved.

    are unstable and can give rise at least to TH1


    cells. Members of the Stockinger laboratory
    recently expanded these observations with
    the help of a mouse expressing Cre recombinase under the control of Il17a regulatory elements. In vivo lineage fate mapping
    revealed that under certain inflammatory
    conditions TH17 cells give rise to TH1 cells
    (M.V. et al., unpublished data). Interestingly,
    these ex-TH17-TH1 cells are distinct from
    de novogenerated TH1 cells in that they
    retain some of their TH17 progenitor program, including the expression of AhR. This
    offers the intriguing possibility that under
    inflammatory conditions during which a
    TH17 celldominated response is reshaped

    into one dominated by TH1 cells, sustained


    AhR activation can result in immune suppression and tolerance (Fig. 1).
    The high toxicity and carcinogenicity associated with TCDD and many other AhR ligands
    would make them unsuitable for any direct
    therapeutic use. In addition, AhR ligands that
    are metabolized by the AhR-initiated system
    may provide only a transient stimulus and
    furthermore, if present at the onset of immune
    activation, are associated with increased onset
    and severity of autoimmunity7,8. This system of
    stimulatory effects on several immune and nonimmune cell types, along with negative feedback
    mechanisms, is highly complex and will require
    much exploration before it is fully understood.

    COMPETING FINANCIAL INTERESTS


    The authors declare no competing financial interests.
    1. Apetoh, L. et al. Nat. Immunol. 11, 854861 (2010).
    2. Gandhi, R. et al. Nat. Immunol. 11, 846853 (2010).
    3. Stumhofer, J.S. et al. Nat. Immunol. 7, 937945
    (2006).
    4. Saraiva, M. & OGarra, A. Nat. Rev. Immunol. 10,
    170181 (2010).
    5. Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D.
    J. Exp. Med. 204, 285297 (2007).
    6. Jankovic, D. et al. J. Exp. Med. 204, 273283
    (2007).
    7. Quintana, F.J. et al. Nature 453, 6571 (2008).
    8. Veldhoen, M. et al. Nature 453, 106109 (2008).
    9. Funatake, C .J. et al. J. Immunotoxicol. 6, 194203
    (2009).
    10. Koch, M.A. et al. Nat. Immunol. 10, 595602 (2009).
    11. Zheng, Y. et al. Nature 458, 351356 (2009).
    12. Veldhoen, M., Hirota, K., Christensen, J., OGarra, A.
    & Stockinger, B. J. Exp. Med. 206, 4349 (2009).

    Innate sensing of nickel


    Marc E Rothenberg
    Although nickel allergy is very common, the specific receptor for nickel has not been identified. TLR4 is now shown
    to bind nickel and cause inflammation, an interaction that is specific to humans.

    ontact sensitivity is an immunological


    hypersensitivity response in the skin that is
    an annoying problemcausing burning, itching,
    redness, swelling and even blistersto millions
    of people worldwide1. Interestingly, the number
    of substances that trigger this response is limited
    compared with the myriad to which the skin is
    exposed. For example, among plants, poison ivy
    is most notorious for inducing contact dermatitis. Among the heavy metals, nickel stands out
    as the chief driver of contact allergy, with up to
    30% of the population being affected2. This is
    most often manifested by allergic skin reactions
    to nickel-containing jewelry (most commonly
    rings and earrings) and, more recently, cellular telephones3 (Fig. 1). Furthermore, nickel
    is of clinical relevance in the context of the
    biocompatibility of cardiovascular stents and
    orthopedic and dental implants.
    An important outstanding question is
    why some substances evoke contact sensitivity whereas most do not. The term nickel
    allergy is really a misnomer, as nickel is not
    a classic allergen that directly induces IgE,
    but rather a hapten that binds to proteins and
    induces delayed-type hypersensitivity cellular responses. Previous work has shown that

    Marc E. Rothenberg is in the Department of


    Pediatrics, Division of Allergy and Immunology,
    Cincinnati Childrens Hospital Medical Center,
    University of Cincinnati College of Medicine,
    Cincinnati, Ohio, USA.
    e-mail: Rothenberg@cchmc.org

    TLR4

    TLR4

    MD2
    MD2
    Ni2+

    Ni2+

    IRF3

    Type I
    IFNs

    NF-B

    Proinflammatory
    molecules

    DTH

    Contact
    allergy

    Nickel-haptenated proteins

    Figure 1 Contact allergy, shown as erythema in this figure, is commonly induced by nickel ions
    present in nickel-containing jewelry such as rings and earrings, as well as in nickel-containing cellular
    telephones. Nickel ion (Ni2+) is shown to bind directly to TLR4, particularly at histidine residues located
    in the region of interaction where TLR4-MD2 molecules form homodimers with one another. This
    binding is sufficient for activation of TLR4 (in the absence of LPS) and the subsequent transcription
    of IRF3 and NF-B. The later production of type I interferons (IFN) and proinflammatory molecules
    provides a necessary and cooperative signal that synergizes with delayed-type hypersensitivity (DTH)
    responses triggered by nickel-haptenated proteins, leading to contact allergy.

    nickel (in the form of nickel salt or ion) is a


    potent stimulator of cellular activation, capable
    of inducing signal transduction in several cell
    types including dendritic cells and endothelial
    cells4. Notably, nickel induces expression of
    proinflammatory genes in endothelial cells,
    a process dependent on induction of NF-B
    activation. This suggests that nickel may
    interact with Toll-like receptor (TLR) signal

    nature immunology volume 11 number 9 SEPTEMBER 2010

    transduction, a critical pathway involved in


    the sensing of pathogen-associated molecular
    patterns and the production of proinflammatory mediators. Progress toward understanding
    nickel allergy has been hindered by the lack of
    mouse modelsas mice do not readily develop
    nickel hypersensitivityas well as by the fact
    that the specific binding protein (or receptor) for nickel has not been identified. These
    781

    2010 Nature America, Inc. All rights reserved.

    news and views


    hindrances may now be erased by the groundbreaking article by Schmidt et al. in this issue
    of Nature Immunology5. The authors have not
    only identified TLR4 as the nickel receptor but
    also elucidated the nickel binding site, and they
    present a model whereby nickel is capable of
    activating TLR4 homodimer formation, leading to signal transduction and production of
    proinflammatory cytokines.
    Using primary human endothelial cells,
    Schmidt et al. first demonstrated that nickel
    indeed induces expression of NF-kB target
    genes such as interleukin 8 (IL-8) by a mechanism dependent upon MyD88 and interleukin 1
    (IL-1) receptorassociated kinase-1 (IRAK1),
    a critical adaptor and signaling molecule,
    respectively linked to receptors of the IL-1
    TLR family. Furthermore, using transfected
    cell lines, the authors demonstrated that
    specific expression of human TLR4 (and
    its co-receptor MD2), but not other human
    TLRs or mouse TLR4, was sufficient for
    responsiveness to nickel (independent of
    lipopolysaccharide (LPS)). Mechanistically,
    the authors identified the specific region of
    human TLR4 that is responsible for nickel
    responses (amino acids 369616). Taking into
    consideration the previously published crystal
    structures of the human TLR4-MD2 complex, which forms a homodimer in the presence of the LPS ligand, the authors focused
    on two nonconserved histidine residues present in this region. On the basis of the known
    role of histidine in binding to charged ions,
    and structural modeling of putative metalbinding sites indicating that the imidazole
    groups of two histidines in this region (His456

    782

    and His458) were at optimal distances to interact with nickel ions, the authors proved that
    nickel specifically interacted with these amino
    acids. Mutagenesis studies demonstrated that
    these two histidines (which are not conserved
    in mouse TLR4) are together required for
    nickel-induced NF-B activation. Notably,
    LPS-induced signaling was unaltered by these
    histidine mutations, showing that nickel and
    LPS use distinct binding sites to TLR4. Further
    elegant experiments showed that the introduction of these two histidine residues into mouse
    TLR4 is sufficient to produce nickel responsiveness. To prove the in vivo relevance of their
    findings, the authors transgenically expressed
    human TLR4 in Tlr4/ mice and demonstrated
    that bone marrowderived macrophages from
    the transgenic mice gained responsiveness to
    nickel. Additionally, these human TLR4
    transgenic mice were readily susceptible to
    induction of experimental allergic contact
    hypersensitivity induced by nickel.
    These results clearly identify nickel as an
    inorganic activator of the TLR system. Whereas
    other contact allergens (such as 2,4,6-trinitrochlorobenzene and oxazolone) seem to interact
    indirectly with TLR2 and TLR4 signaling6, these
    results are the first to show direct triggering
    of pathogen recognition receptors by contact
    allergens. They also explain why current mouse
    models of nickel-induced contact allergy require
    second signals, such as adjuvants. Structurally,
    these findings suggest that nickel may directly
    bridge two adjacent TLR4 molecules, allowing
    a dimer formation similar to that induced by
    LPS, which is sufficient for signal transduction. The finding that nickel binding to TLR4

    occurs at a site distinct from the LPS binding


    site offers a strategy for potentially interfering
    with nickel hypersensitivity while preserving
    TLR4-dependent host responses.
    There are few critical comments to be made
    about these elegant experiments; instead,
    myriad scientific questions and directions now
    emerge. First, what is the interactive relationship between nickel and other TLR4 ligands,
    such as LPS? Second, and related, do other,
    more natural ions known to bind to histidines,
    including protons themselves, influence TLR4
    signaling and/or nickel responses? Do mutations affecting the skin barrier protein filaggrin, which are known to induce susceptibility
    to nickel contact dermatitis7, interact with the
    identified pathway? Does combustion-source
    particulate matter, rich in nickel but negligible
    in LPS content8, mediate lung inflammation by
    nickel-induced TLR4 activation? And finally,
    does my Blackberry contain nickel, or should
    I just get an iPhone?
    COMPETING FINANCIAL INTERESTS
    The author declares no competing financial interests.
    1. Fonacier, L.S., Dreskin, S.C. & Leung, D.Y. J. Allergy
    Clin. Immunol. 125, S138S149 (2010).
    2. Thyssen, J.P. & Menne, T. Chem. Res. Toxicol. 23,
    309318 (2010).
    3. Moennich, J.N., Zirwas, M. & Jacob, S.E. Cutis 84,
    199200 (2009).
    4. Viemann, D. et al. J. Immunol. 178, 31983207
    (2007).
    5. Schmidt, M. et al. Nat. Immunol. 11, 814819 (2010).
    6. Martin, S.F. et al. J. Exp. Med. 205, 21512162
    (2008).
    7. Carlsen, B.C. et al. Contact Dermatitis 63, 8995
    (2010).
    8. Gilmour, P.S., Schladweiler, M.C., Richards, J.H.,
    Ledbetter, A.D. & Kodavanti, U.P. Inhal. Toxicol. 16
    (Suppl. 1), 518 (2004).

    volume 11 number 9 SEPTEMBER 2010 nature immunology

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