KLF14调控单核巨噬细胞糖代谢在脓毒症免疫抑制中的作用

Sepsis-induced immunosuppression is an important cause of the high mortality in septic patients, and monocyte/macrophage dysfunction plays key role in immunosuppression. There are evidences show that the phenotype and function of immune cells are related with the glucose metabolism (glycolysis and oxidative phosphorylation). We found that the expression of Krüppel like factor (KLF14) in peripheral blood monocytes was downregulated, and the secretion of proinflammatory cytokines in septic monocytes was decreased. The result of the experiment in vitro confirmed that the secretion of proinflammatory cytokines and the phagocytic capacity of KLF14 knocked-down macrophages were impaired, furthermore, the expression of the key enzymes of glycolysis in KLF14 knocked-down macrophages were downregulated, but the capacity of the secretion of proinflammatory cytokine could be restored by the glycolytic promoters (high glucose). In order to investigate whether KLF14 affects the function of monocyte/macrophage through regulating glucose metabolism and the possible mechanism during sepsis, our team try to explore the effect of KLF14 on glucose metabolism and cell function of monocyte/macrophage from the septic patients and cells in vitro by the technology of flow cytometry, RNA interference, adenovirus vector transfection and glucose metabolism detection and so on. The purpose of the project is to provide valuable insights into mechanisms of immunosuppression during sepsis and the experimental evidence for the treatment of sepsis in future.

脓毒症免疫抑制是脓毒症患者高死亡率的重要原因，单核巨噬细胞功能障碍在脓毒症免疫抑制中发挥关键作用。有证据表明免疫细胞表型和功能与其糖代谢状态（糖酵解和氧化磷酸化）相关。我们预实验发现脓毒症患者外周血单核细胞Krüppel样因子14（KLF14）表达降低，促炎细胞因子分泌能力下降。体外研究证实KLF14低表达巨噬细胞分泌促炎细胞因子和吞噬能力减弱；进一步发现KLF14低表达巨噬细胞的糖酵解关键酶表达下调，糖酵解促进剂（高糖）部分恢复KLF14低表达巨噬细胞分泌促炎细胞因子的能力。为探讨KLF14是否通过调控糖代谢进而介导脓毒症时单核巨噬细胞功能障碍及其可能机制，本项目将从临床患者及离体细胞水平，应用流式细胞术、RNA干扰、病毒转染、糖代谢检测等技术，探索KLF14对单核巨噬细胞功能及糖代谢的具体影响和可能机制，为加深对脓毒症免疫抑制的认识，寻找脓毒症治疗新的潜在靶点提供实验依据。