Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling

Human Molecular Genetics, Feb 2006

NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase, is essential for NF-κB 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-κB 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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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. - 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)


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Arianna Nenci, Marion Huth, Alfred Funteh, Marc Schmidt-Supprian, Wilhelm Bloch, Daniel Metzger, Pierre Chambon, Klaus Rajewsky, Thomas Krieg, Ingo Haase, Manolis Pasparakis. Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling, Human Molecular Genetics, 2006, pp. 531-542, 15/4, DOI: 10.1093/hmg/ddi470