调节性Langerhans细胞新亚群通过色氨酸代谢负向调控特应性皮炎的作用及机制研究

Langerhans细胞（LC）在特应性皮炎（AD）中发挥关键作用，参与负向调控AD炎症，但确切机制不清。我们前期基于单细胞转录组测序等分析，发现人LC两个主要亚群（LC1和LC2），其中LC2在炎症刺激下易发生活化，高表达免疫抑制分子，诱导调节性T细胞产生，是调节性LC新亚群。进一步分析发现，LC2色氨酸代谢活跃，可能是介导其负向调控作用的机制。我们提出假说认为，AD炎症环境中，调节性LC亚群（LC2）活化并发挥负向调控功能，色氨酸代谢介导了LC2的致耐受作用。本项目拟以人皮肤LC、脐血来源LC和AD模型小鼠为研究对象，明确AD炎症环境中LC亚群的活化情况及色氨酸代谢差异，探索色氨酸代谢调控LC2活化和致耐受的作用和机制，研究靶向LC2-色氨酸代谢对AD小鼠皮肤炎症的作用。本研究首次从代谢角度探索调节性LC新亚群负向调控AD炎症的机制，靶向LC亚群色氨酸代谢有望成为治疗AD的新策略。

Langerhans cells (LCs) play a key role in atopic dermatitis (AD), and participate in the negative regulation of AD inflammation. However, its exact mechanism is still unclear. Based on the analysis of single-cell RNA sequencing of human LCs, our group clarified two principal subpopulations of LCs, LC1 and LC2. We found that LC2 were prone to be activated under the stimulation of inflammatory cytokines, highly expressed immunosuppressive molecules, and induced the production of regulatory T cells, which could be defined as a new subpopulation named “regulatory LC subpopulation”. Our further analysis revealed that LC2 had enhanced tryptophan metabolism compared with LC1, which might be the mechanism of its negative regulation. We put forward the hypothesis that LC2 activate and play a negative regulatory role in the inflammatory microenvironment of AD, which may be mediated by tryptophan metabolism. This project is aimed to study the following aspects using human skin LCs, cord blood-derived LCs and AD mice model: the difference of LC subpopulations in activation level and tryptophan metabolism in AD microenvironment; and role and mechanism of tryptophan metabolism in regulating LC2 activation and inducing its immune tolerance; the effect of targeted LC2-tryptophan metabolism on skin inflammation in the mouse model of AD. According to our knowledge, this project is the first to explore the negative regulation and mechanism of regulatory LC subpopulation in the inflammation of AD. Through the research, we hope that the targeted regulation of tryptophan metabolism in LC2 will become a new strategy for the treatment of AD.