Role of the arylhydrocarbon receptor in hepatic immune regulation

由于其解剖位置，肝脏经常面临潜在的免疫原性肠源性抗原，如营养成分或微生物产品。为了防止针对这些抗原的有害免疫反应，肝脏的免疫反应受到严格的调控。在健康条件下，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细胞反应来维持肝脏的耐受状态。我们假设转录因子芳烃受体(AHR)在肝脏耐受调节中起关键作用，特别是AHR可以调节LSEC和KC的耐受功能。作为一种分子开关，AHR可以在T细胞和抗原提呈细胞中整合来自环境或代谢配体的信号。根据激活的配体，AHR信号可能导致促炎或调节反应。有几个迹象表明AHR在肝脏免疫调节中有特殊的相关性：(1)耐受性AHR配体是由肝细胞特异性酶色氨酸-2，3-双加氧酶组成的。(2)除一般免疫缺陷外，AHR基因敲除小鼠还可出现门静脉肝纤维化和胆管炎性改变。(3)肝内LSEC和KC介导的内毒素耐受是AHR依赖的，本研究的目的是阐明AHR在肝脏免疫调节中的作用。使用具有细胞类型特异性AHR缺陷的条件性基因敲除小鼠将使我们能够选择性地分析LSEC或KC中AHR的免疫学相关性。此外，我们还想评估耐受性AHR配体的应用是否可以用于炎症性肝病的治疗。

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.