芳烃受体募集调节性固有淋巴样细胞在玫瑰痤疮炎症中的作用及分子机制研究

Rosacea is a common and chronic inflammatory skin disease characterized by the presence of facial or ocular inflammation involving both the vascular and tissue stroma. Until recently, the etiology and pathophysiology of this disease were poorly understood. A wide variety of factors from internal and external environment could exacerbate or improve the disease. Recent studies have suggested that aberrant innate immunity is central to this disease. Regulation of the altered innate immunity in rosacea remains unknown. Innate lymphoid cells (ILCs) represent an emerging family of cell types innate immunity. To join the group, a new type of ILC that exhibit regulatory function [known as regulatory ILC (ILCreg)] in innate immunity have also recently been identified.Aryl Hydrocarbon Receptor (AHR) has been identified as a sensor for endogenous and exogenous stimuli and plays an important role in the regulation of inflammatory responses. However, at present, whether AHR or ILCreg contributes to pathogenesis of rosacea is largely undetermined. Our previous studies found that the expression of AHR in rosacea skin was upregulated compared to normal skin. Activation of AHR recruited ILCreg to skin and dampened the severity of inflammatory skin conditions in rosacea mouse model. Therefore, by establishing the animal model of rosacea ，and employing flow cytometry, proteomics- and bioinformatics-associated technologies, this project is designed to investigate alterations of AHR and ILCreg in inflammatory responses of rosacea and to figure out the functional role of AHR and ILCreg in this process. By delineating mechanism of AHR activation and ILCreg recruitment in rosacea, we will gain in-depth knowledge of innate immunity in rosacea, thus explain the benefits of current treatments and set up novel therapeutic strategies for alleviating this disease.

玫瑰痤疮是一种皮肤科常见的慢性炎症性皮肤病。其病因不明，影响因素众多，缺少有效的治疗措施。调节性固有淋巴样细胞（ILCreg）是一类具有免疫调节功能的新型固有淋巴样细胞。芳烃受体（AHR）可感知机体内外多种刺激因素并在炎症反应中发挥重要调节作用。但ILCreg和AHR在玫瑰痤疮中的作用目前还不清楚。我们前期的工作发现玫瑰痤疮皮损中AHR的表达上调，AHR的活化可募集ILCreg至皮损并减轻玫瑰痤疮的炎症反应。基于此，本课题拟以动物模型和临床标本为研究对象，应用流式细胞术、蛋白组学、转基因小鼠及生物信息学分析等技术和方法，探讨AHR和ILCreg在玫瑰痤疮炎症中的作用、关系及分子学机制，借以阐明两者在玫瑰痤疮中的免疫调节功能，揭示其中关键的分子通路。并尝试建立可运用于临床评价诊断、治疗和转归综合评价体系，为玫瑰痤疮的诊断、干预策略和防治模式提供新的视野和切入点。

玫瑰痤疮是一种常见的以固有免疫为主的慢性炎症性皮肤病。其病因不明、影响因素众多缺少有效的治疗措施。固有淋巴样细胞(ILC)是一类新定义的免疫细胞家族，与淋巴细胞一样起源于共同淋巴样祖细胞，不表达重排基因编码的特异性抗原受体,属于固有免疫细胞。研究表明，ILC对于建立早期的固有免疫反应、与表面菌群和过敏原相互作用，在维护组织稳态、抗感染、变态反应和自身免疫性指导的炎症反应等方面发挥着重要的作用。芳烃受体（AHR）被认为是机体内外多种刺激的感受器，并在皮肤炎症反应中发挥着重要调节作用。但不管是ILC还是AHR在玫瑰痤疮的研究中都未有报道。通过对玫瑰痤疮皮损进行生物信息学分析，我们发现AHR在不同类型的玫瑰痤疮皮损中均上调表达。进一步我们建立了玫瑰痤疮小鼠模型，并发现AHR在玫瑰痤疮小鼠模型的表达也显著升高。此外AHR激动剂可诱导小鼠皮肤玫瑰痤疮样的炎症反应，提示AHR在玫瑰痤疮发病过程中发挥重要作用。在适应性免疫缺陷的Rag1-/-小鼠（T细胞和B细胞均缺失的小鼠）中,AHR激动剂也能很好的诱导出玫瑰痤疮样炎症反应，提示AHR诱发玫瑰痤疮炎症反应依赖固有免疫应答。应用流式细胞术分析AHR激动剂诱发的玫瑰痤疮炎症反应的免疫格局提示：AHR可激活3型固有淋巴样细胞(ILC3)的免疫应答。运用CD90.2单克隆抗体敲除固有淋巴样细胞可显著改善AHR诱导的玫瑰痤疮炎症反应。我们的研究结果表明：皮肤中的芳烃受体（AHR）的活化可诱导ILC3相关的炎症反应进而导致玫瑰痤疮的进展，阻断或抑制AHR-ILC3的活化通路及相关分子有可能成为治疗玫瑰痤疮新的切入点。