Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct.
Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct.
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DOI：
10.1038/jid.2013.402
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发表时间：
2014-03
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通讯作者：
K. Vávrová;Dominika Henkes;Kay Strüver;M. Sochorová;Barbora Školová;M. Witting;W. Friess;S. Schreml;R. Meier;M. Schäfer-Korting;J. Fluhr;S. Küchler
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作者：
K. Vávrová;Dominika Henkes;Kay Strüver;M. Sochorová;Barbora Školová;M. Witting;W. Friess;S. Schreml;R. Meier;M. Schäfer-Korting;J. Fluhr;S. Küchler
聚丝蛋白（FLG）基因突变与常见皮肤病如特应性皮炎密切相关。然而，确切的潜在病理机制仍不清楚。在这里，我们使用aFLGknockdown （FLG−）皮肤结构研究了FLG对皮肤脂质组成、组织和皮肤酸化的影响。最初，钠/氢反转运蛋白（NHE-1）活性足以维持重建皮肤的酸性pH值（5.5）。在第7天，FLG降解产物尿尿酸（UCA）和吡烷酮-5-羧酸（PCA）显著降低，但由于NHE-1的上调，皮肤表面pH值仍然是生理的。在第14天，将磷脂转化为脂肪酸的分泌磷脂酶A2(sPLA2) IIA在flg−中的活性明显高于flg +。尽管NHE-1和spla2能够弥补FLG缺陷，维持皮肤表面pH值，并确保神经酰胺加工（未检测到差异），但游离脂肪酸的积累（增加2倍）导致细胞间脂质片层的有序程度降低，FLG -结构的通透性更高。本文描述了UCA/PCA和sPLA2/NHE-1皮肤酸化途径的相互作用，以及FLG不足对重建皮肤中皮肤脂质组成和组织的影响。
Mutations in the filaggrin (FLG) gene are strongly associated with common dermatological disorders such as atopic dermatitis. However, the exact underlying pathomechanism is still ambiguous. Here, we investigated the impact of FLG on skin lipid composition, organization, and skin acidification using aFLGknockdown (FLG−) skin construct. Initially, sodium/hydrogen antiporter (NHE-1) activity was sufficient to maintain the acidic pH (5.5) of the reconstructed skin. At day 7, the FLG degradation products urocanic (UCA) and pyrrolidone-5-carboxylic acid (PCA) were significantly decreased inFLG−constructs, but the skin surface pH was still physiological owing to an upregulation of NHE-1. At day 14, secretory phospholipase A2(sPLA2) IIA, which converts phospholipids to fatty acids, was significantly more activated inFLG−than inFLG+. Although NHE-1 and sPLA2were able to compensate the FLG deficiency, maintain the skin surface pH, and ensured ceramide processing (no differences detected), an accumulation of free fatty acids (2-fold increase) led to less ordered intercellular lipid lamellae and higher permeability of theFLG−constructs. The interplay of the UCA/PCA and the sPLA2/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described.