cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis
cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis
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DOI：
10.1016/j.celrep.2013.09.035
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发表时间：
2013-10-01
期刊：
影响因子：
8.8
通讯作者：
Leverkus, Martin
中科院分区：
文献类型：
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作者：
Panayotova-Dimitrova, Diana;Feoktistova, Maria;Leverkus, Martin
FADD、caspase-8和cFLIP调节细胞死亡信号传导的结果。组成性缺乏这些分子的小鼠在早期胚胎期死亡，而组织特异性FADD或半胱天冬酶-8组成性缺失导致由坏死性凋亡增加引起的炎性皮肤病。cFLIP在体内皮肤中的功能尚不清楚。与组织特异性caspase-8基因敲除相比，我们发现表皮中缺乏cFLIP的小鼠在胚胎第10天和第11天左右死亡。当cFLIP（fl/fl）-K14 CreER（tam）小鼠的成年皮肤中cFLIP表达被废除时，出现了伴随半胱天冬酶活化和凋亡而非坏死性细胞死亡的严重皮肤炎症。细胞凋亡依赖于cFLIP丢失引发的自分泌肿瘤坏死因子的产生。此外，表皮cFLIP蛋白在与表皮细胞凋亡相关的严重药物反应患者中丢失。我们的数据证明了cFLIP对表皮完整性和自发性皮肤炎症沉默的重要性。
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 cFLIP(fl/fl)-K14CreER(tam) 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.