细粒棘球蚴感染小鼠M-MDSC促进Th17分化的机制研究

Cystic echinococcosis, a zoonosis of global distribution caused by the larval stages of Echinococcus granulosus, does serious harm to human. Th17 cell response plays an immunoprotection role in response to Echinococcus granulosus infection, however, the mechanisms that how the hosts regulate the generation of Th17 cells remain unclear. Our previous study found that monocytic myeloid-derived suppressor cells (M-MDSC) that accumulated in the mice infected by Echinococcus granulosus, could promote the differentiation of navie CD4+T cells into Th17 cells, which revealed that M-MDSC promote the generation of Th17 cells in parasite infection.In comparsion of the differentiated expressed genes of M-MDSC post infection with normal M-MDSC, we found that the significant up-regulated expression of resistin-like molecule α (Retnlα) in M-MDSC might invovle in this process. In this study, we aim to further study on the role of Retnlα of M-MDSC in Th17 generation, and also to explore the underlying mechanisms. Our study will explain the regulation mechanisms of host inflammation response against Echinococcus granulosus infection in an in-depth way, and provide novel target for the treatment or drug screening of inflammatory diseases.

细粒棘球蚴病是一种危害严重的人畜共患寄生虫病。Th17细胞反应在宿主抗细粒棘球蚴感染中发挥着免疫保护作用，然宿主免疫系统调控Th17分化的机制尚不明确。本课题组前期研究发现，细粒棘球蚴感染小鼠单核髓源抑制性细胞（M-MDSC）逐渐富集，可明显促进初始CD4+T细胞分化为Th17细胞，表明M-MDSC参与调控宿主Th17分化；比较感染前后M-MDSC差异表达基因，发现 α型抵抗素样分子（Retnlα）表达显著上调，推测其对Th17分化发挥关键作用。本课题拟在此基础上，进一步明确细粒棘球蚴感染小鼠M-MDSC对Th17分化的调控作用，重点阐述M-MDSC上Retnlα的上调表达在促进Th17分化中的作用及机制。本研究将为细粒棘球蚴感染宿主调控炎症反应的机制提供新的见解；也为炎性疾病抗炎治疗策略及药物靶点筛选提供参考。

细粒棘球蚴病是一种危害严重的人畜共患寄生虫病。Th17细胞反应在宿主抗细粒棘球蚴感染中发挥着免疫保护作用，然宿主免疫系统调控Th17分化的机制尚不明确。本课题发现，细粒棘球蚴感染可诱导M-MDSC（单核髓源抑制性细胞）促进初始CD4+T 细胞分化为Th17细胞，而MDSC的另一个亚群—G-MDSC（多核髓源抑制性细胞）并无明显此调控作用；进一步研究显示，感染小鼠M-MDSC表达α型抵抗素样分子（Retnl α，又称为HIF-1α）明显上调，其上游PI3K/AKT1被活化，而mTOR通路被抑制，细胞代谢以糖酵解为主，可能为其促进Th17分化更为快速地提供能量。并且，感染小鼠M-MDSC的转录与趋化因子表达均明显下调，是其分化和功能异常的重要原因。本课题还发现，细粒棘球绦虫原头节（Echinococcus granulosus protoscoleces，EgPSC），可分泌一些分泌排泄物（excretory-secretory products，ESPs），抑制初始CD4+T 细胞分化为Th17细胞。以上研究结果提示，Retnl α介导调控细粒棘球蚴感染小鼠M-MDSC的糖代谢重编程事件，而后者可能是M-MDSC调节T细胞免疫反应的重要基础。本研究为寄生虫调控宿主免疫应答的机制提供了新的见解。