Hönzke Stefan, Wallmeyer Leonie, Ostrowski Anja, Radbruch Moritz, Mundhenk Lars, Schäfer-Korting Monika, Hedtrich Sarah
Institute for Pharmaceutical Sciences, Pharmacology & Toxicology, Freie Universität Berlin, Germany.
Department of Veterinary Pathology, Freie Universität Berlin, Germany.
J Invest Dermatol. 2016 Mar;136(3):631-639. doi: 10.1016/j.jid.2015.11.007. Epub 2015 Nov 19.
Atopic dermatitis is a chronic skin condition with complex etiology. It is characterized by skin barrier defects and T helper type 2 (Th2)-polarized inflammation. Although mutations in the filaggrin gene are known to be prominent genetic risk factors for the development of atopic dermatitis, the interdependency between these and an altered cytokine milieu is not fully understood. In this study, we evaluated the direct effects of filaggrin deficiency on the cornified envelope, tight junction proteins, and innate immune response, and report the effects of Th2 cytokines in normal and filaggrin-deficient skin equivalents. Supplementation with IL-4 and IL-13 led to distinct histologic changes and significantly increased skin surface pH, both of which were enhanced in filaggrin knockdown skin equivalents. We detected a compensatory up-regulation of involucrin and occludin in filaggrin-deficient skin that was dramatically disturbed when simultaneous inflammation occurred. Furthermore, we found that a lack of filaggrin triggered an up-regulation of human ?-defensin 2 via an unknown mechanism, which was abolished by Th2 cytokine supplementation. Taken together, these results indicate that defects in the epidermal barrier, skin permeability, and cutaneous innate immune response are not primarily linked to filaggrin deficiency but are rather secondarily induced by Th2 inflammation.
特应性皮炎是一种病因复杂的慢性皮肤疾病。其特征为皮肤屏障缺陷和2型辅助性T细胞（Th2）极化炎症。尽管已知丝聚合蛋白基因的突变是特应性皮炎发生的主要遗传风险因素，但这些因素与细胞因子环境改变之间的相互依存关系尚未完全明确。在本研究中，我们评估了丝聚合蛋白缺乏对角质包膜、紧密连接蛋白和固有免疫反应的直接影响，并报告了Th2细胞因子在正常和丝聚合蛋白缺乏的皮肤替代物中的作用。补充白细胞介素-4和白细胞介素-13导致了明显的组织学变化，并显著提高了皮肤表面pH值，这两者在丝聚合蛋白敲低的皮肤替代物中均有所增强。我们检测到在丝聚合蛋白缺乏的皮肤中兜甲蛋白和闭合蛋白有代偿性上调，而当同时发生炎症时这种上调受到显著干扰。此外，我们发现丝聚合蛋白的缺乏通过一种未知机制触发了人β-防御素2的上调，而补充Th2细胞因子可消除这种上调。综上所述，这些结果表明表皮屏障、皮肤通透性和皮肤固有免疫反应的缺陷并非主要与丝聚合蛋白缺乏相关，而是继发于Th2炎症。
