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cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis

Diana Panayotova-Dimitrova, Maria Feoktistova, Michaela Ploesser

    Cell Reports
    |November 12, 2013
    PubMed

    Insights

    Cellular FLICE-inhibitory protein (cFLIP) is crucial for skin integrity. Loss of cFLIP in the epidermis triggers severe inflammation and apoptosis, highlighting its role in preventing spontaneous skin inflammation.

    Area of Science:

    • Immunology
    • Cell Biology
    • Dermatology

    Background:

    • FADD, caspase-8, and cFLIP are key regulators of cell death signaling pathways.
    • Constitutive absence of these molecules leads to embryonic lethality, while tissue-specific deletion of FADD or caspase-8 causes inflammatory skin disease due to increased necroptosis.

    Purpose of the Study:

    • To investigate the in vivo function of cFLIP in the skin.
    • To determine the consequences of cFLIP deficiency in epidermal cells.

    Main Methods:

    • Generation and analysis of mice with constitutive epidermal cFLIP deficiency.
    • Inducible deletion of cFLIP in adult mouse epidermis using cFLIPfl/fl-K14CreERtam model.
    • Assessment of skin inflammation, caspase activation, and cell death (apoptosis and necroptosis).
    • Analysis of cFLIP expression in patient skin samples from severe drug reactions.

    Main Results:

    • Constitutive epidermal cFLIP deficiency resulted in embryonic lethality around days 10-11.
    • Abrogation of cFLIP in adult skin induced severe inflammation, caspase activation, and apoptosis, but not necroptosis.
    • Epidermal apoptosis was driven by autocrine tumor necrosis factor (TNF) signaling.
    • Loss of epidermal cFLIP protein was observed in patients with severe drug reactions involving epidermal apoptosis.

    Conclusions:

    • cFLIP is essential for maintaining epidermal integrity and preventing spontaneous skin inflammation.
    • Epidermal cFLIP acts as a critical suppressor of TNF-induced apoptosis.
    • Dysregulation of cFLIP contributes to inflammatory skin conditions, including severe drug reactions.

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