Role of the arylhydrocarbon receptor in hepatic immune regulation

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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.