成纤维网状细胞通过LTβR/NIK信号通路调控慢性肾脏病中三级淋巴结构形成的作用及其机制研究

三级淋巴结构（TLS）是慢性肾脏病（CKD）患者肾脏中淋巴细胞聚集的特殊结构，然而目前肾脏TLS形成机制尚不明确。申请者前期发现，CKD患者肾脏TLS比例越高预后越差；在TLS小鼠模型中，淋巴毒素、成纤维网状细胞（FRC）比例及其来源的CXCL13和CCL19表达水平增高，肾脏LTβR/NIK通路被激活，LTβR受体定位于FRC而敲除LTβR可减少肾脏TLS形成；同时，在肾脏原代FRC中，淋巴毒素能促进该细胞分泌CXCL13和CCL19。这些结果提示FRC可能通过LTβR/NIK途径调节肾脏TLS的形成。为此，本项目拟明确淋巴毒素、FRC和趋化因子在CKD患者肾脏中的表达及临床意义，并利用LTβR基因敲除鼠和GP38/LTβR中和抗体，从细胞和动物水平探讨FRC调控CKD中TLS形成的作用机制，及其与LTβR/NIK信号通路的关联。本项目为TLS的形成机制和CKD的防治提供新颖的理论依据。

Tertiary lymphoid structure (TLS) is a special structure where lymphocytes accumulate in the kidneys of patients with chronic kidney disease (CKD). However, the mechanism of kidney TLS formation is currently unclear. The applicant found in the early stage that the higher the proportion of kidney TLS in CKD patients, the worse the prognosis; in the TLS mouse model, the proportion of lymphotoxin, fibroblasts (FRC) and the expression levels of CXCL13 and CCL19 derived from FRC increased, and the kidney LTβR/NIK The pathway is activated, the LTβR receptor is localized in FRC and knocking out LTβR can reduce the formation of TLS in the kidney; at the same time, in the primary kidney FRC, lymphotoxin can promote the cell to secrete CXCL13 and CCL19. These results suggest that FRC may regulate the formation of renal TLS through the LTβR/NIK pathway. To this end, this project intends to clarify the expression and clinical significance of lymphotoxin, FRC and chemokines in the kidneys of CKD patients, and use LTβR knockout mice and GP38/LTβR neutralizing antibodies to explore FRC's regulation of the formation of TLS CKD at the cellular and animal levels and its association with the LTβR/NIK signaling pathway. This project provides a novel theoretical basis for the mechanism of TLS formation and the prevention and treatment of CKD.