Aryl Hydrocarbon Receptor in Keratinocytes Is Essential for Murine Skin Barrier Integrity
Aryl Hydrocarbon Receptor in Keratinocytes Is Essential for Murine Skin Barrier Integrity
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DOI：
10.1016/j.jid.2016.06.627
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发表时间：
2016-11-01
影响因子：
6.5
通讯作者：
Esser, Charlotte
中科院分区：
文献类型：
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作者：
Haas, Katharina;Weighardt, Heike;Esser, Charlotte
芳烃受体（AhR）是一种参与适应性细胞功能的配体激活的转录因子，并且其在表皮中高度活跃。AhR配体可以加速角质形成细胞分化，但AhR在皮肤屏障中的确切作用尚不清楚。我们的研究表明，经表皮水分流失，皮肤屏障完整性的参数，是高AhR缺陷小鼠。条件性AhR缺陷小鼠系的实验确定角质形成细胞为负责高经表皮水分损失的主要细胞群。电子显微镜显示AhR基因敲除小鼠角质形成细胞表皮细胞间连接较弱，基因表达分析确定了许多屏障相关基因作为AhR靶点。此外，AhR缺陷小鼠的微生物组具有更高的个体间差异。有趣的是，从野生型小鼠的饮食中去除AhR配体模仿了AhR缺陷，相对于受损的屏障;相反，重新添加植物来源的配体吲哚-3-甲醇挽救了屏障缺陷，即使在老年小鼠中。我们的研究结果表明，功能性AhR表达是皮肤屏障完整性的关键，AhR代表了皮肤屏障疾病的治疗方法，包括饮食干预的发展的分子靶点。
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in adaptive cell functions, and it is highly active in the epidermis. AhR ligands can accelerate keratinocyte differentiation, but the precise role of AhR in the skin barrier is unknown. Our study showed that transepidermal water loss, a parameter of skin barrier integrity, is high in AhR-deficient mice. Experiments with conditionally AhR-deficient mouse lines identified keratinocytes as the primary cell population responsible for high transepidermal water loss. Electron microscopy showed weaker intercellular connectivity in the epidermis of keratinocytes in AhR-knockout mice, and gene expression analysis identified many barrier-associated genes as AhR targets. Moreover, AhR-deficient mice had higher interindividual differences in their microbiome. Interestingly, removing AhR ligands from the diet of wild-type mice mimicked AhR deficiency with respect to the impaired barrier; conversely, re-addition of the plant-derived ligand indole-3-carbinol rescued the barrier deficiency even in aged mice. Our results suggest that functional AhR expression is critical for skin barrier integrity and that AhR represents a molecular target for the development of therapeutic approaches for skin barrier diseases, including by dietary intervention.