Role of the arylhydrocarbon receptor in hepatic immune regulation

由于肝脏的解剖位置，肝脏经常面对潜在的免疫原性肠道来源抗原，如营养成分或微生物产物。为了防止针对这些抗原的有害免疫反应，肝脏中的免疫反应受到严格调节。在健康状态下，肝窦内皮细胞（LSEC）和库普弗细胞（KC）通过分泌抗炎介质和抑制炎症T细胞反应来维护肝脏耐受状态的维持。我们假设转录因子芳烃受体（AHR）在肝脏耐受性的调节中起关键作用，特别是AHR可以调节LSEC和KC的耐受性功能。作为一个分子开关，AHR可以整合T细胞和抗原提呈细胞中来自环境或代谢配体的信号。依赖于激活配体，AHR信号可能导致促炎或调节反应。有几个提示指向AHR在肝脏免疫调节中的特殊相关性：(1)耐受性AHR配体由肝细胞特异性酶色氨酸-2,3-双加氧酶组成。(2)除一般免疫缺陷外，AHR基因敲除小鼠还会出现门脉肝纤维化和胆管炎症改变。(3)肝脏中LSEC和KC介导的内毒素耐受性已被证明是ahr依赖性的。本研究旨在阐明AHR在肝脏免疫调节中的作用。使用具有细胞类型特异性AHR缺陷的条件敲除小鼠，将使我们能够选择性地分析AHR在LSEC或KC中的免疫学相关性。此外，我们希望评估耐受性AHR配体的应用是否可能用于治疗炎症性肝病。

Due to its anatomical location, the liver is constantly confronted with potentially immunogenic gut-derived antigens such as nutritional components or microbial products. To prevent harmful immune reactions against such antigens, immune responses in the liver are tightly regulated.Under healthy conditions, liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC) safeguard the maintenance of a tolerant state in the liver by secretion of anti-inflammatory mediators and suppression of inflammatory T cell responses.We hypothesize that the transcription factor arylhydrocarbon receptor (AHR) is critically involved in the regulation of hepatic tolerance, and in particular, that AHR can modulate tolerogenic functions of LSEC and KC. As a molecular switch, AHR can integrate signals from environmental or metabolic ligands, both in T cells and antigen presenting cells. Dependenton the activating ligands, AHR signalling may result in a proinflammatory or regulatory response.There are several hints that point to a particular relevance of AHR in hepatic immune regulation: (1) Tolerogenic AHR ligands are constitutively produced by the hepatocyte-specific enzyme Tryptophan-2,3-Dioxygenase. (2) Besides general immune defects, AHR knockout mice develop portal liver fibrosis and inflammatory alterations of the bile ducts. (3) Endotoxin tolerancethat is mediated by LSEC and KC in the liver has been shown to be AHR-dependent.The aim of this research proposal is to elucidate the role of AHR in hepatic immune regulation. The use of conditional knockout mice with cell type-specific AHR deficiency will allow us to selectively analyse the immunological relevance of AHR in LSEC or KC. Moreover, we wantto evaluate whether the application of tolerogenic AHR ligands might serve the therapy of inflammatory liver disease.