Functional Characterization of Lymphotoxin-beta-Rezeptor Activation in Inflammation

淋巴素β受体（LTβR）是TNF受体家族的一员，其功能与异源三聚体配体LTα1β2或同源三聚体配体LIGHT相互作用，均在活化淋巴细胞上表达。相反，LTβR在淋巴细胞和NK细胞上不表达，但在成纤维细胞、上皮细胞和髓系细胞上表达。我们之前的研究表明，LTβR/配体相互作用似乎是下调和控制急性dss诱导结肠炎模型肠道炎症的必要条件。我们最近使用骨髓嵌合体的结果证实了我们最初的假设，即造血细胞上LTβR的激活在抑制dss诱导的肠道炎症中起着至关重要的作用。此外，我们已经成功地培育了条件LTβR缺陷小鼠（LysMCre x LTβR flox/flox），特异性地消融了LTβR基因在单核/巨噬细胞和中性粒细胞上的表达。这些小鼠在我们的实验模型中表现出增强的炎症反应。基于这些结果，我们将通过使用CD11c-Cre缺失小鼠与LTβR flox/flox小鼠杂交来评估LTβR激活对树突状细胞的潜在作用，以确定哪种髓细胞类型参与控制炎症反应。通过表征LTβR刺激后的细胞反应和分子机制，我们能够证明LTβR激活后TRIM30对脑源性巨噬细胞的特异性诱导。目前已有报道称TRIM30负性调节tlr介导的NFκB激活，似乎介导了一种负性调节反馈机制来控制过度炎症。我们将描述相关细胞群中ltβ r依赖性诱导TRIM30的分子机制。此外，通过详细分析LTβR激活后细胞间和细胞内的分子机制，将表征负责反调节炎症反应的新型效应机制。

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.