AHR as a master regulator in cutaneous and systemic autoimmunity

系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病，影响包括皮肤、关节、中枢神经系统或肾脏在内的许多器官。尽管SLE的病理生理学机制尚不完全清楚，但已有研究表明，细胞凋亡清除受损、先天和获得性免疫反应上调、补体激活、自身抗体以及包括1型干扰素在内的促炎细胞因子的不平衡产生的相互作用导致了自身耐受性的丧失。系统性红斑狼疮的发病需要遗传易感性、环境诱因以及免疫和激素因素的综合作用。在系统性红斑狼疮的环境诱因中，紫外线是最公认的诱因。紫外光照射有助于色氨酸光产物的产生，色氨酸光产物是芳香烃受体(AHR)的内源性配体，芳烃受体是一种经常被认为是外部刺激传感器的转录因子。除了紫外线，饮食化合物或毒素，其中许多被称为系统性红斑狼疮的危险因素，代表AHR配体，因此，转录的激活与自身免疫性疾病有关。为了研究AHR在系统性自身免疫中的作用，我们建立了一种SLE小鼠模型(K14-CD40L TG小鼠)，该模型模拟了人类疾病的典型特征，包括自身免疫性皮炎、肾炎、血清中的自身抗体和自身反应性T细胞的存在。有趣的是，AHR信号对疾病的发展至关重要，因为培育成AHR缺乏背景的K14-CD40L TG小鼠没有表现出任何类似SLE的自身免疫症状。细胞类型特异性的AHR缺失表明，T细胞中的AHR信号与CD40L诱导的自身免疫的发生似乎没有太大关系，而朗格林+树突状细胞(DC)中AHR缺失的小鼠则完全免受疾病侵袭，这表明AHR在组织驻留DC中起着中心作用。因此，我们假设AHR可能通过调节免疫细胞的功能，如组织内树突状细胞，在(系统性)自身免疫性疾病的发生和发展中起关键作用。现在，我们将试图更好地了解AHR信号在自身免疫发病过程中的配体和细胞特异性特征，并将解决三个核心问题：(1)AHR信号在自身免疫的发生和发展中的影响以及自身反应细胞中该通路的功能相关性；(2)干预AHR信号作为自身免疫疾病(辅助)治疗的潜在治疗选择；(3)AHR信号通路与致病或自身反应人类细胞发育的相关性。综上所述，该项目旨在更好地了解自身免疫过程中AHR的相互作用，这可能导致使用这种可药物配体激活的转录因子作为局部或辅助治疗自身免疫性疾病的分子靶点的新策略。

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting many organs including the skin, the joints, the central nervous system or the kidneys. Although the pathophysiology of SLE is not completely understood yet, it has been shown that the interaction of impaired apoptotic clearance, up-regulated innate and adaptive immune responses, complement activation, autoantibodies, and imbalanced production of pro-inflammatory cytokines including type-1 interferons leads to the loss of self-tolerance. The onset of SLE requires a combination of genetic predisposition, environmental triggers, and immunological as well as hormonal factors. Among the environmental triggers of SLE, ultraviolet (UV) light is the most recognized one. UV irradiation contributes to the generation of tryptophan photoproducts, which act as endogenous ligands of the aryl hydrocarbon receptor (AHR), a transcription factor frequently suggested as sensor of external stimuli. Besides UV, dietary compounds or toxins, many of which are known as risk factors of SLE, represent AHR ligands and thus, activation of the transcription has been linked to autoimmune disorders. To investigate the role of AHR in systemic autoimmunity we generated a mouse model for SLE (K14-CD40L TG mice), which mimics typical characteristics of human disease including autoimmune dermatitis, nephritis, autoantibodies in the serum, and the presence of autoreactive T cells. Interestingly, AHR signaling was critical for disease development since K14-CD40L TG mice bred to an AHR-deficient background did not show any symptoms of SLE-like autoimmunity. Cell type-specific deletion of AHR revealed that AHR signaling in T cells seemed to be of minor relevance for the onset of CD40L-induced autoimmunity whereas mice deficient for AHR in Langerin+ dendritic cells (DC) were completely protected from disease, suggesting a central role of AHR in tissue-resident DC. Hence, we hypothesized that AHR might be critically involved in the development and progression of (systemic) autoimmune diseases by modulating the function of immune cells such as tissue-resident DC. Now we will try to better understand the ligand- and cell-specific character of AHR signaling during the onset of autoimmunity and three central questions shall be addressed: (1) Impact of AHR signaling on the development and progression of autoimmunity as well as functional relevance of the pathway in autoreactive cells; (2) Intervention in AHR signaling as potential therapeutic option for an (adjuvant) treatment of autoimmune diseases; (3) Relevance of the AHR pathway for the development of pathogenic or autoreactive human cells. Taken together, the project aims at better understanding AHR interactions in autoimmune processes, which might result in novel strategies to use this druggable ligand-activated transcription factor as a molecular target for the local or adjuvant treatment of autoimmune diseases.