title: Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling.
abstract: NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase, is essential for NF-kappaB 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-kappaB 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.
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory, via Ramarini 32, 00016 Monterotondo-Scalo, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Nenci
authors.forename: Marion
authors.initials: M
authors.lastname: Huth
authors.forename: Alfred
authors.initials: A
authors.lastname: Funteh
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency* / Q000378:metabolism; D007184:Incontinentia Pigmenti / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase