芳香烃受体在皮肤共生菌群调控特应性皮炎免疫应答中的作用及机制研究

Currently, microbiota has been the hot topic of the field of immunology and related disciplines, and the progress on skin microbiota has changed our view on the relationship between atopic dermatitis (AD) and skin infections. It has been revealed that skin microbiota contribute to immune homeostasis of the skin, and regulate the immune response elicited by skin injury and infection. Our group found that the inflammation of AD mouse model aggravated when there was a lower level of skin microbiota. The inflammation of AD model alleviated after live Staphylococcus epidermidis (SE) were applied topically; however, there was no apparent effect of dead bacteria. These study suggested that metabolites of skin bacteria might play an important role in the regulation of AD inflammation. However, the exact mechanism is not clear yet. Aryl hydrocarbon receptor (AhR) can sense environmental pollutants and bacterial metabolites, and regulates skin inflammation via keratinocytes (KC). We propose that skin metabolites could activate AhR and regulate skin immune response and participate in the pathogenesis of AD. We plan to use the mouse model deficient in AhR to produce AD mouse model, and to analyze the role of AhR in the regulation of AD inflammation by skin bacteria metabolites. We also plan to analyze the cell types that Ahr exert its function, and analyze the ligand of AhR, the downstream signaling pathway and interacting molecules. We hope the current proposal could help to further our understanding on the role of skin microbiota in the pathogenesis of AD.

共生菌群是目前免疫学及相关学科的研究热点，其中皮肤菌群的研究更新了以往关于特应性皮炎(AD)与皮肤感染关系的认识。研究发现皮肤菌群影响皮肤免疫稳态，调控外伤、感染等炎症介导的应答；我们发现皮肤菌群减少后小鼠经皮致敏AD模型炎症加重，外用活的表皮葡萄球菌后AD炎症减轻，而死菌无作用，提示细菌代谢产物在调控AD炎症中发挥作用，但确切的受体机制尚不明确。芳香烃受体(AhR)是机体感受环境污染物和细菌代谢产物的重要受体，参与多种免疫细胞及角质形成细胞(KC)的功能调控。我们提出假说认为，细菌代谢产物通过活化AhR而调控皮肤免疫应答并参与AD发病。本研究拟利用缺失AhR的模式小鼠，制备经皮致敏AD模型，分析AhR在皮肤菌群调控AD免疫应答中的作用，分析基于AhR发挥作用的细胞类型，分析AhR的配体、下游分子及与TLR等模式识别受体通路的相互作用，为阐明皮肤菌群在AD发病中的作用和机制进行积极的探索。

共生菌群是目前免疫学及相关学科的研究热点，其中皮肤菌群与特应性皮炎(AD)的相关性受到了越来越多的关注，但皮肤菌群在AD发病中的确切作用和机制尚不明确。基于以往发现的皮肤菌群在维持皮肤稳态中的作用，以及芳香烃受体(AhR)作为机体感受环境污染物和细菌代谢产物的重要受体对角质形成细胞(KC)的功能调控，我们提出假说认为，细菌代谢产物通过活化AhR而调控皮肤免疫应答并参与AD发病。本研究首先分析了AD患者皮肤菌群的特征及功能，发现AD患者皮肤菌群色氨酸代谢功能下降；进而分析了AD患者皮损与非皮损皮肤表面色氨酸及其代谢产物的含量，发现AD皮肤表面具有一定含量的色氨酸，色氨酸的菌群代谢产物吲哚-3-甲醛(IAId)的含量在AD患者显著低于正常人；将IAId外用于MC903诱导的AD小鼠模型，发现其显著抑制AD的皮肤炎症，表现为大体炎症减轻、皮肤内炎症细胞浸润减少、血清IgE水平降低等；进一步利用AhR活化抑制剂及AhR基因敲除小鼠，发现IAId对AD样皮炎的抑制作用依赖于AhR的活化；体外KC培养水平的实验发现，IAId通过结合于AhR抑制TSLP的转录和表达；IAId的这一抑制作用仅限于MC903诱导的AD样皮炎，对于咪喹莫特诱导的银屑病样皮炎或恶唑酮诱导的接触性超敏反应则没有抑制作用。IAId还可以促进Langerhans细胞(LC)表达IL-10和IDO，调控皮肤炎症及KC应答。本研究首次揭示了皮肤菌群代谢产物在AD炎症中的作用，为基于皮肤菌群及其代谢产物开发防治AD的药物奠定了基础。