HMGB1通过TLR4/NF-κB信号通路介导1型糖尿病鼠胰岛细胞损伤的机制研究

Type 1 diabetes (T1D) is characterized by permanent damage of islet cells, the cause of which has not yet been elucidated. It has been confirmed that the occurrence and development of T1D is often associated with increased inflammatory factors and activation of inflammatory signaling pathway. Our previous study has found that: ①the proinflammatory factor, high mobility group box 1(HMGB1), which was upregulated in the mouse pancreas, promoted the development of T1D, but the specific mechanism of which was unknown; ②HMGB1 receptor toll like receptor 4 (TLR4) was located on the surface of islet cells, while the receptor associated NF-κB signaling pathways was involved in the damage of islet cells. To determine whether HMGB1 activates NF-κB signaling pathway and participates in the mechanism of T1D by damaging islet cells through its receptor and/or inducing the release of inflammatory cytokines. The mouse model of T1D will be used in our research. HMGB1 will be overexpressed or inhibited in vivo. Meanwhile, the islet cells will be separated, and different concentrations of HMGB1, different receptors and pathway inhibitors will be added in islet cells in vitro. Overall, we will clarify the mechanism of HMGB1 in T1D by TLR4/NF-κB signaling pathway from four levels including animals, tissues, cells and molecules, which will help to find the target of damaged islet cells and provide a novel viewpoint for the management of T1D.

1型糖尿病（T1D）以胰岛细胞的永久性破坏为特征，病因迄今尚未阐明。已证实，T1D的发生、发展常伴随炎症因子的增多和炎症信号通路的激活。我们前期研究发现:①致炎因子高迁移率族蛋白B1（HMGB1）在T1D小鼠胰腺内表达水平上调并促进T1D的进展，但具体机制不详；②胰岛细胞膜表面存在HMGB1的受体toll样家族受体4（TLR4），而与该受体相关的信号通路NF-κB和胰岛细胞的损伤有关。为探索HMGB1是否通过TLR4/NF-κB信号通路参与T1D胰岛细胞损伤，本研究拟构建T1D小鼠模型，在体内过表达或抑制HMGB1；同时在体外分离胰岛细胞并对其分别予以不同浓度HMGB1刺激和不同受体及通路阻断剂，从动物、组织、细胞及分子四个层面上阐明HMGB1介导TLR4/NF-κB信号通路致T1D的机制，为进一步寻找胰岛细胞损伤的靶点及防治T1D提供新的理论依据。

1型糖尿病（T1D）以胰岛细胞的永久性破坏为特征，病因迄今尚未阐明。已证实，T1D的 .发生、发展常伴随炎症因子的增多和炎症信号通路的激活。我们前期研究发现：致炎因子高迁移率族蛋白B1（HMGB1）在T1D小鼠胰腺内表达水平上调并促进T1D的进展。为探索HMGB1是否通过TLR4/NF-κB信号通路参与T1D胰岛细胞损伤，本研究构建T1D小鼠模型，在体内过表达或抑制HMGB1；同时在体外分离胰岛细胞并对其分别予以不同浓度HMGB1刺激和不同受体及通路阻断剂，从动物、组织、细胞及分子四个层面上阐明HMGB1介导TLR4/NF-κB信号通路致T1D的机制。本研究发现:①T1D小鼠胰腺HMGB1表达量明显增加，且胰岛细胞中HMGB1蛋白由胞核向胞外转移明显增多；②胰岛细胞膜表面存在HMGB1的受体toll样家族受体4（TLR4），HMGB1通过结合其高亲和力受体TLR4，继而通过激活NF-κB信号通路而致胰岛细胞损伤，损伤的胰岛细胞释放出HMGB1并形成正反馈；此外，释放到外周血中的HMGB1也加重了炎性反应，促进了T1D的进展。通过抑制TLR4/NF-κB通路，阻断炎症反应的恶性循环，有助于缓解胰岛细胞内过度失控的炎症反应，为进一步寻找胰岛细胞损伤的靶点及T1D的防治提供新思路。