cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis

• Published in: Cell reports (Cambridge) 2013-10, Vol.5 (2), p.397-408
• Main Authors: Panayotova-Dimitrova, Diana, Feoktistova, Maria, Ploesser, Michaela, Kellert, Beate, Hupe, Mike, Horn, Sebastian, Makarov, Roman, Jensen, Federico, Porubsky, Stefan, Schmieder, Astrid, Zenclussen, Ana Claudia, Marx, Alexander, Kerstan, Andreas, Geserick, Peter, He, You-Wen, Leverkus, Martin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; CASP8 and FADD-Like Apoptosis Regulating Protein - deficiency; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Caspase 8 - genetics; Caspase 8 - metabolism; Cells, Cultured; Homeostasis; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Skin - metabolism; Skin - pathology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.09.035

FADD, caspase-8, and cFLIP regulate the outcome of cell death signaling. Mice that constitutively lack these molecules die at an early embryonic age, whereas tissue-specific constitutive deletion of FADD or caspase-8 results in inflammatory skin disease caused by increased necroptosis. The function of cFLIP in the skin in vivo is unknown. In contrast to tissue-specific caspase-8 knockout, we show that mice constitutively lacking cFLIP in the epidermis die around embryonic days 10 and 11. When cFLIP expression was abrogated in adult skin of cFLIPfl/fl-K14CreERtam mice, severe inflammation of the skin with concomitant caspase activation and apoptotic, but not necroptotic, cell death developed. Apoptosis was dependent of autocrine tumor necrosis factor production triggered by loss of cFLIP. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. Our data demonstrate the importance of cFLIP for the integrity of the epidermis and for silencing of spontaneous skin inflammation. [Display omitted] [Display omitted] •Constitutive lack of epidermal cFLIP causes embryonic lethality•Postnatal ablation of cFLIP results in skin inflammation and caspase activation•Epidermal apoptosis upon acute cFLIP loss is TNF dependent•Human cutaneous drug reactions (TEN/SJS) are associated with loss of epidermal cFLIP The function of the caspase-8 inhibitor cFLIP in the skin in vivo is unknown. Leverkus and colleagues show that a constitutive lack of epidermal cFLIP is embryonically lethal. When cFLIP expression was abrogated in adult epidermis, skin inflammation, caspase activation, and tumor-necrosis-factor-dependent apoptotic cell death developed. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. The results demonstrate the importance of cFLIP for epidermal integrity and silencing of spontaneous skin inflammation.