Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling
Arianna Nenci
2
Marion Huth
2
Alfred Funteh
1
Marc Schmidt-Supprian
0
Wilhelm Bloch
4
Daniel Metzger
3
Pierre Chambon
3
Klaus Rajewsky
0
Thomas Krieg
1
Ingo Haase
1
Manolis Pasparakis
2
0
CBR Institute for Biomedical Research, Harvard Medical School
, 200 Longwood Avenue,
Boston, MA 02115, USA
1
Department of Dermatology, Center for Molecular Medicine, University of Cologne (CMMC)
, Joseph- Stelzmann-Strasse 9,
50924 Cologne, Germany
2
European Molecular Biology Laboratory, Mouse Biology Unit
, via Ramarini 32, 00016 Monterotondo-Scalo (
Rome
),
Italy
3
Institut de Ge ne tique et de Biologie Mole culaire et Cellulaire (IGBMC)
, CNRS, INSERM, ULP,
and Institut Clinique de la Souris (ICS)
, BP 10142-67404, ILLKIRCH, C.U. de Strasbourg,
France
4
Abteilung fu r Molekulare und Zellula re Sportmedizin, Deutsche Sporthochschule Ko ln, IG I, Carl-Diem-Weg 6, D-50933 Ko ln,
Germany
NF-kB essential modulator (NEMO), the regulatory subunit of the IkB kinase, is essential for NF-kB activation. Mutations disrupting the X-linked NEMO gene cause incontinentia pigmenti (IP), a human genetic disease characterized by male embryonic lethality and by a complex pathology affecting primarily the skin in heterozygous females. The cellular and molecular mechanisms leading to skin lesion pathogenesis in IP patients remain elusive. Here we used epidermis-specific deletion of NEMO in mice to investigate the mechanisms causing the skin pathology in IP. NEMO deletion completely inhibited NF-kB activation and sensitized keratinocytes to tumor necrosis factor (TNF)-induced death but did not affect epidermal development. Keratinocyte-restricted NEMO deletion, either constitutive or induced in adult skin, caused inflammatory skin lesions, identifying the NEMO-deficient keratinocyte as the initiating cell type that triggers the skin pathology in IP. Furthermore, genetic ablation of tumor necrosis factor receptor 1 (TNFRI) rescued the skin phenotype demonstrating that TNF signaling is essential for skin lesion pathogenesis in IP. These results identify the NEMO-deficient keratinocyte as a potent initiator of skin inflammation and provide novel insights into the mechanism leading to the pathogenesis of IP.
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The NF-kB transcription factors control the expression of
many genes with important functions in inflammation,
immune responses, cell proliferation, survival and apoptosis
(1,2). In resting cells, NF-kB dimers are kept inactive by
association with inhibitory proteins belonging to the IkB
family. NF-kB activation is induced by the IkB kinase
(IKK) complex consisting of the IKK1(IKKa) and
IKK2(IKKb) catalytic subunits and the NF-kB essential
modulator (NEMO)/IKKg regulatory protein (3 5). Upon
activation by a variety of stimuli, including proinflammatory
cytokines such as tumor necrosis factor (TNF) and interleukin-1
(IL-1) and bacterial lipopolysaccharide (LPS), the IKK
phosphorylates IkB proteins at specific serine residues targeting
them for polyubiquitination and proteasome-mediated
degradation, thus releasing NF-kB, which then accumulates in the
nucleus and activates its target genes (6,7). IKK2 and
NEMO are essential for NF-kB activation by proinflammatory
signals via the classical activation pathway, whereas IKK1 is
required for the alternative NF-kB activation pathway
controlling p100 processing (8).
Several studies have suggested that the NF-kB pathway is
involved in the regulation of epidermal homeostasis (9,10).
Inhibition of NF-kB activation in epidermal keratinocytes
either by transgenic overexpression of a mutant
nondegradable IkBa or by knockout of the p65 NF-kB subunit
lead to epidermal hyperplasia, suggesting a growth-regulatory
role for NF-kB in keratinocytes (10 15). Furthermore, Dajee
et al. (13) showed that inhibition of NF-kB in combination
with expression of oncogenic Ras in human keratinocytes
transplanted on the skin of severe combined
immunodeficiency (SCID) mice caused the development of invasive
tumors resembling squamous cell carcinoma. In a different
study, overexpression of IkB in the epidermis of transgenic
mice caused an inflammatory hyperproliferative epidermal
phenotype leading to the development of squamous cell
carcinomas (16,17). In this case, however, blockade of TNF
signaling inhibited both epidermal hyperplasia and tumor formation,
suggesting that the development of squamous cell carcinomas
in this model depends on a TNF-induced inflammatory
response (18). Mice with epidermis-specific deletion of
IKK2 display an inflammatory skin phenotype characterized
by expression of proinflammatory cytokines and chemokines,
infiltration of immune cells, epidermal hyperplasia and
deregulated expression of epidermal differentiation markers
(19). Also in this case, genetic ablation of TNF signaling
rescued the skin phenotype demonstrating that the epidermal
hyperplasia is a secondary effect of the inflammatory response.
In humans, mutations disrupting the X-linked gene
encoding NEMO cause incontinentia pigme (...truncated)