UMR5165 CNRS, U1056 INSERM, University of Toulouse, Department of Dermatology, University Hospital of Toulouse, Toulouse, France.
J Allergy Clin Immunol. 2013 Apr;131(4):1094-102. doi: 10.1016/j.jaci.2012.12.1566. Epub 2013 Feb 10.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG).
We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD.
An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25.
Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels.
The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction.
特应性皮炎（AD）是一种慢性炎症性皮肤病，其特征是表皮屏障紊乱。在一部分患者中，这种情况是由编码丝聚合蛋白（FLG）的基因中的无义突变引起的。
我们试图评估 FLG 突变和促炎细胞因子的各自作用，并评估 FLG、兜甲蛋白（HRNR）和 FLG2 的表达，FLG2 是参与表皮屏障功能的 2 种 FLG 样蛋白，在 AD 患者的正常皮肤以及病变和非病变皮肤中。
使用免疫组织化学和免疫印迹法分析了 73 例成年 AD 患者和 73 名年龄匹配的对照者的 FLG 基因分型队列。正常的原代人角质形成细胞在缺乏或存在 IL-4、IL-13 和 IL-25 的情况下进行分化。
与对照者相比，AD 患者的皮肤中无论其 FLG 基因型如何，FLG、HRNR 和 FLG2 的表达均明显降低。与非病变皮肤相比，病变皮肤中的降低更为明显。此外，野生型患者的皮肤中 proFLG/FLG 比值高于对照者。细胞因子处理角质形成细胞导致 FLG、FLG2 和 HRNR 的表达在 mRNA 和蛋白水平上均显著降低。
AD 成人病变皮肤和临床未受影响的皮肤的角质层均异常，FLG 和 FLG 样蛋白表达减少。除了无义突变，促炎细胞因子和一些 proFLG 加工缺陷也可能导致 FLG 下调。我们的研究表明，皮肤炎症会降低 FLG 样蛋白的表达，导致 AD 相关的表皮屏障功能障碍。
