Zingkou Eleni, Reynier Marie, Pampalakis Georgios, Serre Guy, Jonca Nathalie, Sotiropoulou Georgia
Department of Pharmacy, School of Health Sciences, University of Patras, Rion, 26504 Patras, Greece.
Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), CNRS, Toulouse University, Inserm, 31024 Toulouse, France.
Int J Mol Sci. 2025 Sep 4;26(17):8605. doi: 10.3390/ijms26178605.
Congenital ichthyoses, now grouped under the acronym EDD (Epidermal Differentiation Disorders), include nonsyndromic forms (nEDD) that may be caused by loss-of-function mutations in the gene encoding corneodesmosin (-nEDD, formerly Peeling skin syndrome type 1). It is characterized by skin peeling, inflammation, itching and food allergies, while no specific therapy is currently available. High levels of KLK5, the serine protease that initiates the desquamation cascade, are found in the epidermis of -nEDD patients. Thus, we hypothesized that KLK5 inhibition would alleviate the symptoms of -nEDD and could serve as a new pharmacological target. A human epidermal equivalent (HEE) model for -nEDD was developed using shRNA-mediated knockdown. This model was characterized and used to assess the role of KLK5 knockdown on -nEDD. Also, mice were crossed with mice, the murine model of -nEDD, to examine in vivo the effect(s) of deletion in -nEDD. Both models recapitulated the -nEDD desquamating phenotype. Elimination of KLK5 aggravated the -nEDD phenotype. Epidermal proteolysis was surprisingly elevated, while severe ultrastructural (corneo)desmosomal alterations increased epidermal barrier permeability and detachment was manifested. Based on these results, we concluded that targeting epidermal proteolysis with ablation cannot compensate for the loss of corneodesmosin and rescue over-desquamation of the -nEDD. Possibly, in the absence of KLK5, other proteases take over which increases the severity of over-desquamation in . The translational outcome is that over-desquamation may not always be rescued by eliminating epidermal proteolysis, but fine protease modulation is more likely required.
先天性鱼鳞病，现归类于首字母缩写为EDD（表皮分化障碍）的疾病组，包括非综合征型（nEDD），其可能由编码角质桥粒蛋白的基因突变导致功能丧失引起（-nEDD，以前称为1型剥脱性皮肤综合征）。其特征为皮肤脱皮、炎症、瘙痒和食物过敏，而目前尚无特异性治疗方法。在-nEDD患者的表皮中发现了高水平的KLK5，即启动脱屑级联反应的丝氨酸蛋白酶。因此，我们推测抑制KLK5可缓解-nEDD的症状，并可作为一个新的药理学靶点。利用短发夹RNA介导的敲低技术建立了-nEDD的人表皮等效模型（HEE）。对该模型进行了表征，并用于评估敲低KLK5对-nEDD的作用。此外，将小鼠与-nEDD的小鼠模型进行杂交，以在体内研究-nEDD中基因缺失的影响。两种模型均重现了-nEDD的脱屑表型。消除KLK5会加重-nEDD表型。令人惊讶的是，表皮蛋白水解作用增强，同时严重的超微结构（角质）桥粒改变增加了表皮屏障通透性，并出现了细胞脱落。基于这些结果，我们得出结论，通过基因消融靶向表皮蛋白水解不能弥补角质桥粒蛋白的缺失，也无法挽救-nEDD的过度脱屑。在缺乏KLK5的情况下，可能有其他蛋白酶取而代之，从而增加了-nEDD中过度脱屑的严重程度。转化结果是，过度脱屑可能并不总是能通过消除表皮蛋白水解来挽救，而更可能需要精细的蛋白酶调节。
