cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis
Authors
Diana Panayotova-Dimitrova, Maria Feoktistova, Michaela Ploesser, Beate Kellert, Mike Hupe, Sebastian Horn, Roman Makarov, Federico Jensen, Stefan Porubsky, Astrid Schmieder, Ana Claudia Zenclussen, Alexander Marx, Andreas Kerstan, Peter Geserick, You-Wen He, and Martin Leverkus
Institution
University Heidelberg
Country
Germany
Year
2013
Journal
Cell
Abstract
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