皮肤菌群代谢产物IAId修复皮肤屏障功能抑制特应性皮炎的作用及机制研究

Skin barrier abnormalities play an essential role in atopic dermatitis (AD). The skin bacteria and its metabolites are important components of the skin barrier, but its specific role in the pathology and physiology of AD is not clear. Our study found that a less content of indol-3-aldehyde (IAId), a bacterial metabolite of tryptophan, in the skin lesions of AD. In the MC903 induced AD-like model, topical application of IAId onto mice skin decreased the levels of inflammatory cytokines, reduced the transepidermal water loss (TEWL) and inhibited the inflammation of AD, but its mechanism is not clear now. We further found that IAId could also decrease the TEWL in the tape-stripping model which characterized by impaired skin barrier, suggesting that IAId may directly repair the skin barrier which contributes to the inhibition of AD inflammation. Aryl hydrocarbon receptor (AhR) has been proved to be an important pathway for maintaining barrier function. We found that IAId can activate AhR on keratinocytes. Therefore, we infer that the involvement of IAId-AhR on repairing skin barrier is an important mechanism in inhibiting AD. Based on this, we intend to use 3D skin model, AhR knockout mice and shRNA cell transfection technology to clarify the role and mechanism of IAId-AhR axis in the skin barrier, aiming to provide a theory for the treatment of AD with microbial metabolites.

皮肤屏障功能障碍是特应性皮炎(AD)发病的关键环节，菌群及其代谢产物是构成皮肤屏障的重要部分，但其在AD的病理、生理意义尚不清楚。我们发现AD患者皮损处菌群的色氨酸代谢产物——吲哚-3-甲醛（IAId）含量减少，MC903诱导AD炎症后，皮肤涂抹IAId可以抑制炎症分子的表达，降低小鼠的经皮水丢失（TEWL），抑制AD的炎症，其具体机制尚不清楚。我们进一步发现，在胶布粘贴诱导的皮肤受损模型中，IAId可抑制TEWL，提示IAId可能是通过直接修复皮肤屏障发挥抑制AD炎症的作用。芳香烃受体（AhR）是调节器官屏障功能的重要通路，我们发现IAId可以激活角质形成细胞上的AhR，因此我们推断IAId-AhR参与修复皮肤屏障是抑制AD的重要机制。因此，本课拟利用3D皮肤模型、AhR敲除鼠及shRNA细胞转染技术等明确IAId-AhR轴在皮肤屏障中的作用和机制，为利用菌群代谢治疗AD提供理依据。

皮肤屏障功能障碍是特应性皮炎(Atopic dermatitis, AD)发病的关键环节，菌群及其代谢产物是构成皮肤屏障的重要部分，但其在AD的病理、生理意义尚不清楚。我们发现AD患者皮损处菌群的色氨酸代谢产物——吲哚-3-甲醛（Indol-3-aldehyde, IAId）含量显著减少，卡泊三醇（Calcipotriene，MC903）诱导AD炎症后，皮肤涂抹IAId可以抑制炎症分子的表达，降低小鼠的经皮水丢失（Transepidermal water loss，TEWL）水平，但其具体机制尚不清楚。我们通过RNAseq结果分析发现IAId可以显著抑制脂肪酸合成关键分子——甾醇调节元件结合蛋白1（Sterol response element-binding protein 1，SREBP1）及其下游靶分子的表达。基于此，首先我们明确了SREBP1是参与AD炎症反应、损伤皮肤屏障的关键分子；进而发现IAId通过抑制SREBP1的表达发挥削弱AD炎症、修复皮肤屏障的作用；最后，通过体外实验表明，IAId抑制SREBP1相关分子表达的作用依赖于芳香烃受体信号通路。该研究明确了IAId-AhR轴在皮肤屏障中的作用和机制，为利用菌群代谢治疗AD提供理依据。