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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(M.V. et al., unpublished data).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.
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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