Kezic Sanja, Jakasa Ivone
Curr Probl Dermatol. 2016;49:1-7. doi: 10.1159/000441539. Epub 2016 Feb 4.
The skin barrier function is greatly dependent on the structure and composition of the uppermost layer of the epidermis, the stratum corneum (SC), which is made up of flattened anucleated cells surrounded by highly organized and continuous lipid matrix. The interior of the corneocytes consists mainly of keratin filaments aggregated by filaggrin (FLG) protein. Next, together with several other proteins, FLG is cross-linked into a mechanically robust cornified cell envelope providing a scaffold for the extracellular lipid matrix. In addition to its role for the SC structural and mechanical integrity, FLG degradation products account in part for the water-holding capacity and maintenance of acidic pH of the SC, both crucial for the epidermal barrier homoeostasis by regulating activity of multiple enzymes that control desquamation, lipid synthesis and inflammation. The major determinant of FLG expression in the skin are loss-of-function mutations in FLG, the strongest genetic risk factor for atopic dermatitis (AD), an inflammatory skin disease characterized by a reduced skin barrier function. The prevalence of FLG mutations varies greatly among different populations and ranges from about 10% in Northern Europeans to less than 1% in the African populations. An impaired skin barrier facilitates absorption of potentially hazardous chemicals, which might cause adverse effects in the skin, such as contact dermatitis, or systemic toxicity after their passage into blood. In another direction, a leaky epidermal barrier will lead to enhanced loss of water from the skin. A recent study has shown that even subtle increase in epidermal water loss in newborns increases the risk for AD. Although there are multiple modes of action by which FLG might affect skin barrier it is still unclear whether and how FLG deficiency leads to the reduced skin barrier function. This chapter summarizes the current knowledge in this field obtained from clinical studies, and animal and in vitro models of FLG deficiency.
皮肤屏障功能很大程度上依赖于表皮最上层即角质层（SC）的结构和组成，角质层由扁平无核细胞组成，周围环绕着高度有序且连续的脂质基质。角质形成细胞内部主要由角蛋白丝组成，这些角蛋白丝由兜甲蛋白（FLG）聚合而成。接下来，FLG与其他几种蛋白质一起交联形成机械强度高的角质化细胞包膜，为细胞外脂质基质提供支架。除了对SC结构和机械完整性的作用外，FLG降解产物部分解释了SC的持水能力和酸性pH值的维持，这两者对于通过调节控制脱屑、脂质合成和炎症的多种酶的活性来维持表皮屏障稳态至关重要。皮肤中FLG表达的主要决定因素是FLG功能丧失突变，这是特应性皮炎（AD）最强的遗传风险因素，AD是一种以皮肤屏障功能降低为特征的炎症性皮肤病。FLG突变的患病率在不同人群中差异很大，从北欧人的约10%到非洲人群的不到1%不等。受损的皮肤屏障会促进潜在有害化学物质的吸收，这些化学物质可能会对皮肤造成不良影响，如接触性皮炎，或进入血液后产生全身毒性。另一方面，渗漏的表皮屏障会导致皮肤水分流失增加。最近一项研究表明，即使新生儿表皮水分流失的细微增加也会增加患AD的风险。尽管FLG可能通过多种作用方式影响皮肤屏障，但目前仍不清楚FLG缺乏是否以及如何导致皮肤屏障功能降低。本章总结了该领域从临床研究以及FLG缺乏的动物和体外模型中获得的现有知识。
