| Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO-deficiency in epidermal keratinocytes and requires TNF signaling (2006) | |||||||||||||
Abstract | |||||||||||||
| 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 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 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 incontinentia pigmenti. | |||||||||||||
Publication details | |||||||||||||
| |||||||||||||