补体C5a/C5aR信号调控CD45+红系前体细胞免疫抑制功能及其机制研究

Infection prevention and management of patients with late stage tumor is a priority in clinic. Previous studies indicated that C5a/C5aR signaling promote immune response against bacterial infection in tumor-free organism. However, our data suggest that C5a/C5aR signaling promote immune inhibition in mice with late stage tumors and lead to an increase in mortality of bacteria infection. Mechanically, we identified CD45+erythroid progenitor cells (CD45+EPCs) as robust immunosuppressors in blood and spleens, which was induced by tumor burden associated extramedullary hematopoiesis. Massive generation of C5a was also induced by growth of tumor burden. CD45+EPCs express high-level C5aR, which was involved in regulation of its suppressive activity. In this study, we will study the underlying mechanism by which C5a/C5aR signaling regulate ROS expression and release, by using RNA-Seq、Western-blot、Flow-cytomety etc. Finally, we will demonstrate the clinical significance of plasma C5a level.

晚期肿瘤病人感染的控制和预防是亟待解决的临床免疫学问题。在正常机体中，补体C5a/C5aR信号在感染免疫中发挥重要的保护作用。然而我们的前期研究结果却证实：在晚期荷瘤小鼠体内，C5a/C5aR促进了荷瘤小鼠系统性免疫抑制，并导致其在细菌感染中死亡率显著上升。机制上，我们发现：随着肿瘤负荷的增加，小鼠脾脏和血液中出现了一群具有重要免疫抑制功能的CD45+红系前体细胞（CD45+EPCs）的大量聚集，伴随着小鼠外周血和脾脏中的C5a水平显著升高。CD45+EPCs高表达C5aR，并且C5aR信号促进了CD45+EPCs免疫抑制功能。本项目拟对C5a/C5aR信号对CD45+EPCs的ROS表达的影响及其分子机制进行研究，以RNA-Seq、Western-blot、FACS等手段研究C5aR如何调控CD45+EPCs的ROS表达，并最终阐明肿瘤病人血浆C5a的临床意义。

晚期肿瘤病人感染的控制和预防是亟待解决的临床免疫学问题。在正常机体中，补体C5a/C5aR信号在感染免疫中发挥重要的保护作用。然而我们的前期研究结果却证实：在晚期荷瘤小鼠体内，C5a/C5aR促进了荷瘤小鼠系统性免疫抑制，并导致其在细菌感染中死亡率显著上升。机制上，我们发现：随着肿瘤负荷的增加，小鼠脾脏和血液中出现了一群具有重要免疫抑制功能的CD45+红系前体细胞（CD45+EPCs）的大量聚集，伴随着小鼠外周血和脾脏中的C5a水平显著升高。人和小鼠的CD45+EPCs均高表达C5aR，并且C5aR信号促进了CD45+EPCs免疫抑制功能及其在脾脏部位的聚集。当阻断C5aR信号后，晚期荷瘤小鼠对系统性感染的抵抗能力显著增强。

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