GPR174调控肠道树突状细胞功能影响脓毒症肠道免疫的机制研究

GPR174作为重要的免疫相关基因，调节机体炎症反应。前期我们发现GPR174基因变异与脓毒症易感性和肠道功能障碍相关；并且Gpr174敲除可减轻脓毒症小鼠肠道炎症损伤和保持菌群稳态。进一步研究发现，Gpr174KO脓毒症小鼠肠道树突状细胞(DC)表型和成熟度与野生鼠不同，体外实验发现Gpr174影响骨髓源性DC成熟，调控T细胞增值和分化。DC是重要的抗原递呈细胞，调节肠道免疫反应。Gpr174是否影响肠道DC迁移和调控T细胞分化，从而在肠道炎症损伤过程中发挥作用？本研究拟利用DC特异性Gpr174敲除小鼠，探讨以下问题: Gpr174对脓毒症小鼠肠道DC成熟、迁移影响；对肠系膜淋巴结DC调控T细胞增值和分化影响；CCL21-Gpr174-Gα轴影响DC迁移的机制；基础和临床研究相结合，探讨Gpr174是否通过DC改善脓毒症肠道损伤、维持菌群稳态和肠道代谢，为脓毒症肠道损伤治疗寻找新靶点。

As a immune-related gene, G-protein coupled receptor 174 (GPR174) might play an essential role in regulating the inflammatory response. Our previous study showed that genetic variants in GPR174 were associated with the susceptibility of sepsis and intestinal dysfunction. Gpr174 deficiency attenuated intestinal injury and altered intestinal microbiota composition in septic mice after cecal ligation and puncture (CLP). Further study revealed that the phenotype and maturity of the intestinal dendritic cells(DC) in Gpr174KO mice differed from that of wild mice, which is supported by the evidence that GPR174 down-regulated the expression of co-stimulatory molecules such as CD80 and CD86 in bone marrow-derived dendritic cells (BMDCs) and consequently suppressed naive CD4+T cells proliferation and differentiation in vitro. Dendritic cells(DC) are antigen-presenting cells involved in maintaining intestinal immune homeostasis. However, it remains unclear whether GPR174 inhibits intestinal mucosa dendritic cells migration to mesenteric lymph nodes (MLN), and influences T cell proliferation and differentiation.The underlying mechanism needs to be elucidated. In the current study, we aim to answer the following questions through further study using CD11c-cre+-Gpr174f/f mice. First, to investigate whether Gpr174 influences intestinal dendritic cells maturity and migration during sepsis. Second, to identify whether Gpr174 is involved in the interaction of intestinal dendritic cells with T cells, which alter T cells proliferation and differentiation. Third, to investigate the role of CCL21-Gpr174-Gα axis in intestinal DC migration. Last, to clarify whether Gpr174 deficiency alleviates intestinal injury and regulates intestinal flora and metabolism via DC in sepsis progress. Gpr174 may be a new target for the treatment of intestinal injury in sepsis.