Acute modulations in permeability barrier function regulate epidermal cornification - Role of caspase-14 and the protease activated receptor type 2
Acute modulations in permeability barrier function regulate epidermal cornification - Role of caspase-14 and the protease activated receptor type 2
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DOI：
10.2353/ajpath.2008.070161
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发表时间：
2008-01-01
影响因子：
6
通讯作者：
Feingold, Kenneth R.
中科院分区：
文献类型：
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作者：
Demerjian, Marianne;Hachem, Jean-Pierre;Feingold, Kenneth R.
角质层包含角质细胞，其在终末分化过程中源自外颗粒层，嵌入富含脂质的细胞外基质中，由表皮层状体分泌。渗透性屏障损伤刺激预先形成的层状体从外颗粒层快速分泌，通过调节离子梯度和丝氨酸蛋白酶 (SP)/蛋白酶激活受体 2 型 (PAR2) 信号传导进行调节。由于屏障功能也需要角质细胞，因此我们假设角质细胞的形成也可能受到屏障功能的调节。通过两种不相关的方法消除屏障引发了角质化波，通过电子显微镜评估为颗粒层中 TdT 介导的 dUTP 缺口末端标记阳性细胞和新角质化细胞。由于角质化被闭塞所阻断，因此角质细胞专门根据屏障而不是损伤或细胞替换的要求而形成。 SP 抑制剂和过度酸化（降低 SP 活性）在屏障破坏后阻止角质化。类似地，PAR2(-/-)小鼠的角化被延迟。尽管细胞凋亡的经典标志物 [聚 (ADP-核糖) 聚合酶和 caspase (Carp)-3] 保持不变，但屏障破坏激活了 Casp-14。此外，泛Casp抑制剂Z-VAD-FMK延迟了Casp14(-/-)小鼠的角质化，并且角质细胞结构异常。因此，渗透性屏障的要求以 SP 和 Casp-14 依赖性方式协调驱动角质层富含脂质的细胞外基质的生成和颗粒细胞向角质细胞的转化，由 PAR2 发出信号。
Stratum corneum comprises corneocytes, derived from outer stratum granulosum during terminal differentiation, embedded in a lipid-enriched extracellular matrix, secreted from epidermal lamellar bodies. Permeability barrier insults stimulate rapid secretion of preformed lamellar bodies from the outer stratum granulosum, regulated through modulations in ionic gradients and serine protease (SP)/protease-activated receptor type 2 (PAR2) signaling. Because corneocytes are also required for barrier function, we hypothesized that corneocyte formation could also be regulated by barrier function. Barrier abrogation by two unrelated methods initiated a wave of cornification, assessed as TdT-mediated dUTP nick end-labeling-positive cells in stratum granulosum and newly cornified cells by electron microscopy. Because cornification was blocked by occlusion, corneocytes formed specifically in response to barrier, rather than injury or cell replacement, requirements. SP inhibitors and hyperacidification (which decreases SP activity) blocked cornification after barrier disruption. Similarly, cornification was delayed in PAR2(-/-) mice. Although classical markers of apoptosis [poly(ADP-ribose)polymerase and caspase (Carp)-3] remained unchanged, barrier disruption activated Casp-14. Moreover, the pan-Casp inhibitor Z-VAD-FMK delayed cornification, and corneocytes were structurally aberrant in Casp14(-/-) mice. Thus, permeability barrier requirements coordinately drive both the generation of the stratum corneum lipid-enriched extracellular matrix and the transformation of granular cells into corneocytes, in an SP- and Casp-14-dependent manner, signaled by PAR2.