Functional Characterization of Lymphotoxin-beta-Rezeptor Activation in Inflammation

光敏素-β-受体（LTβR）是TNF受体家族的一员，在功能上与异源三聚体配体LTα1β2或同源三聚体配体LIGHT相互作用，两者均表达于活化的淋巴细胞上。相反，LTβR在淋巴细胞和NK细胞上不表达，但在成纤维细胞、上皮细胞和髓源性细胞上表达。我们的前期研究表明，LTβR/配体相互作用对于DSS诱导的急性结肠炎模型中肠道炎症的下调和控制是必要的。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，我们已经成功地产生了条件性LTβ R缺陷小鼠（LysMCre x LTβR flox/flox），其特异性消除了单核细胞/巨噬细胞和中性粒细胞上的LTβR基因表达。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CD 11 c-Cre删除小鼠与LTβR flox/flox小鼠杂交来评估LTβR活化对树突状细胞的潜在作用，以确定哪种髓样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BM源性巨噬细胞后TRIM 30的特异性诱导。迄今为止，TRIM 30已被报道负调节TLR介导的NFκB活化，并且似乎介导负调节反馈机制以控制过度炎症。我们将描述相关细胞群中LTβ R依赖性诱导TRIM 30的分子机制。此外，负责反调节炎症反应的新效应机制将通过详细分析LTβR激活后的细胞间和细胞内分子机制来表征。

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.