Acute Acidification of Stratum Corneum Membrane Domains Using Polyhydroxyl Acids Improves Lipid Processing and Inhibits Degradation of Corneodesmosomes
Acute Acidification of Stratum Corneum Membrane Domains Using Polyhydroxyl Acids Improves Lipid Processing and Inhibits Degradation of Corneodesmosomes
复制标题
DOI：
10.1038/jid.2009.249
复制
发表时间：
2010-02-01
影响因子：
6.5
通讯作者：
Elias, Peter M.
中科院分区：
文献类型：
--
作者：
Hachem, Jean-Pierre;Roelandt, Truus;Elias, Peter M.
正常酸性的角质层（SC）的中和对通透性屏障稳态以及SC的完整性/内聚力具有有害影响，这是由于丝氨酸蛋白酶（SPs）的激活导致脂质加工酶和角质桥粒（CD）的失活/降解。由于升高的pH会损害SC的结构和功能，我们在此探讨SC过度酸化是否会改善其结构和功能。我们使用两种多羟基酸（PHA），即乳糖酸（LBA）或葡糖酸内酯（GL）来降低小鼠SC的pH。PHA的应用降低了无毛小鼠SC所有层面的pH，并进一步选择性酸化了SC膜结构域，如荧光寿命成像所示。过度酸化改善了通透性屏障稳态，这归因于两种关键的膜定位的、产生神经酰胺的水解酶（β - 葡萄糖脑苷脂酶和酸性鞘磷脂酶）活性增加，这与SC片层膜的细胞外成熟加速相关。过度酸化产生了“超常”的SC完整性/内聚力，这归因于SP依赖性的桥粒芯糖蛋白 - 1（DSG1）降解减少以及在SC下层诱导DSG3表达。由于SC过度酸化改善了即使是正常表皮的结构和功能，这些研究为评估SC酸化作为炎症性皮肤病的一种治疗策略的潜在效用奠定了基础，炎症性皮肤病的特征是屏障功能、内聚力和表面pH异常。
Neutralization of the normally acidic stratum corneum (SC) has deleterious consequences for permeability barrier homeostasis and SC integrity/cohesion attributable to serine proteases (SPs) activation leading to deactivation/degradation of lipid-processing enzymes and corneodesmosomes (CD). As an elevated pH compromises SC structure and function, we asked here whether SC hyperacidification would improve the structure and function. We lowered the pH of mouse SC using two polyhydroxyl acids (PHA), lactobionic acid (LBA), or gluconolactone (GL). Applications of the PHA reduced the pH at all levels of SC of hairless mouse, with further selective acidification of SC membrane domains, as shown by fluorescence lifetime imaging. Hyperacidification improved permeability barrier homeostasis, attributable to increased activities of two key membrane-localized, ceramide-generating hydrolytic enzymes (beta-glucocerebrosidase and acidic sphingomyelinase), which correlated with accelerated extracellular maturation of SC lamellar membranes. Hyperacidification generated "supernormal'' SC integrity/cohesion, attributable to an SP-dependent decreased degradation of desmoglein-1 (DSG1) and the induction of DSG3 expression in lower SC. As SC hyperacidification improves the structure and function, even of normal epidermis, these studies lay the groundwork for an assessment of the potential utility of SC acidification as a therapeutic strategy for inflammatory dermatoses, characterized by abnormalities in barrier function, cohesion, and surface pH.