Functional Characterization of Lymphotoxin-beta-Rezeptor Activation in Inflammation

• Antragsteller: Professor Dr. Thomas Hehlgans
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2007 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 34814745

The Lymphotoxin-β-Receptor (LTβR), a member of the TNF receptor family, functionally interacts with the heterotrimeric ligand LTα1β2 or the homotrimeric ligand LIGHT, both expressed on activated lymphocytes. In contrast, the LTβR is not expressed on lymphocytes and NK cells but is expressed on fibroblasts, epithelial cells and cells of myeloid origin. Our previous studies demonstrated that LTβR/ligand interaction seems to be necessary for downregulation and controlling intestinal inflammation in the model of acute DSS-induced colitis. Our recent results using bone marrow chimeras confirmed our initial hypothesis that activation of the LTβR on hematopoietic cells plays a crucial role in dampening DSS-induced intestinal inflammation. Furthermore, we have successfully generated conditional LTβR-deficient mice (LysMCre x LTβR flox/flox) with specific ablation of LTβR gene expression on monocytes/macrophages and neutrophils. These mice demonstrated an enhanced inflammatory reaction in our experimental model. Based on these results we will assess the potential role of LTβR activation on dendritic cells by using CD11c-Cre deleter-mice crossed to LTβR flox/flox mice in order to determine which myeloid cell type is involved in controlling the inflammatory reaction. By characterizing the cellular responses and molecular mechanisms after LTβR stimulation, we were able to demonstrate the specific induction of TRIM30 after LTβR activation on BM-derived macrophages. So far TRIM30 has been reported to negatively regulate TLR-mediated NFκB activation and seems to mediate a negative regulatory feedback mechanism to control excessive inflammation. We will characterize the molecular mechanisms involved in the LTβR-dependent induction of TRIM30 in the relevant cell populations. Furthermore, novel effector mechanisms responsible for counter-regulating the inflammatory reaction will be characterized by analyzing inter- and intra-cellular molecular mechanisms after LTβR activation in detail.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 876: Mechanisms dampening inflammation