Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation
Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation
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DOI：
10.1038/ncb1560
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发表时间：
2007-04-01
影响因子：
21.3
通讯作者：
Pasparakis, Manolis
中科院分区：
文献类型：
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作者：
Gareus, Ralph;Huth, Marion;Pasparakis, Manolis
先前报道激酶IKK 1（也称为IKK α）通过在角质形成细胞中起作用以NF-κ B非依赖性方式诱导其分化来调节表皮发育和骨骼形态发生（1-5）。在这里，我们表明，表皮角质形成细胞特异性IKK 1消融（以下简称IKK 1（EKO））的小鼠发展正常分化的分层表皮，表明IKK 1诱导表皮分化的功能不是角质形成细胞自主的。尽管正常的表皮分层，IKK 1（EKO）小鼠显示受损的表皮屏障功能和增加的经表皮水分流失，由于角质层脂质组成和表皮紧密连接的缺陷。这些缺陷是由IKK 1缺陷表皮中编码关键脂质修饰酶和紧密连接蛋白的视黄酸靶基因失调引起的。此外，我们发现IKK 1缺陷细胞显示受损的视黄酸诱导的基因转录，IKK 1被招募到视黄酸调节基因的启动子，这表明IKK 1控制表皮屏障形成的一种机制是通过调节角质形成细胞中视黄酸受体靶基因的表达。
The kinase IKK1 (also known as IKK alpha) was previously reported to regulate epidermal development and skeletal morphogenesis by acting in keratinocytes to induce their differentiation in an NF-kappa B independent manner(1-5). Here, we show that mice with epidermal keratinocyte-specific IKK1 ablation (hereafter referred to as IKK1(EKO)) develop a normally differentiated stratified epidermis, demonstrating that the function of IKK1 in inducing epidermal differentiation is not keratinocyte-autonomous. Despite normal epidermal stratification, the IKK1(EKO) mice display impaired epidermal-barrier function and increased transepidermal water loss, due to defects in stratum corneum lipid composition and in epidermal tight junctions. These defects are caused by the deregulation of retinoic acid target genes, encoding key lipid modifying enzymes and tight junction proteins, in the IKK1-deficient epidermis. Furthermore, we show that IKK1-deficient cells display impaired retinoic acid-induced gene transcription, and that IKK1 is recruited to the promoters of retinoic acid-regulated genes, suggesting that one mechanism by which IKK1 controls epidermal-barrier formation is by regulating the expression of retinoic acid receptor target genes in keratinocytes.