LC3相关吞噬在低钾环境下对T细胞分化调节在肠道免疫防御及细菌移位中的作用

Hypokalemia is one of the risk factors of peritoneal dialysis related enterobacteriaceae peritonitis. LC3-associated phagocytosis (LAP) is an efficient process of host cell phagocytosis and pathogens degradation, which can exert cellular immune response by regulating T cell proliferation, differentiation and producing effector T cells. We found that intestinal microbial homeostasis was destroyed and bacterial translocation occurred in hypokalemia mice model, and the expression of LAP-specific protein NOX2 was significantly decreased. Furthermore, abnormal differentiation balance of CD4+T cells was found in peritoneal dialysis patients with hypokalemia. However, it is not clear the role of LAP and CD4+T cell balance in intestinal immune function and bacterial translocation, or whether they existed relationship. We hypothesize that impaired LAP pathway under low potassium environment will lead to CD4+T cell balance destroy, which together lead to the impairment of intestinal immune defense and eventually result in bacterial translocation. Based on previous research, this study intends to explore the role of LAP in intestinal immune function and bacterial translocation under low potassium environment, reveals the potential mechanism of low potassium on enterobacteriaceae peritonitis from the perspective of immune defense, and provides experimental evidence for peritonitis prevention and treatment.

低钾血症是腹膜透析相关性腹膜炎的危险因素。LC3 相关吞噬作用(LC3-associated phagocytosis, LAP)是宿主细胞吞噬和降解病原体的高效过程，并且具有抗原提呈效应，可调控T细胞增生、分化及产生效应T细胞发挥免疫应答效应。我们研究发现，低钾血症小鼠肠道微生物稳态遭到破坏，并发生细菌移位，而肠壁LAP特异性蛋白NOX2表达下降；在合并低钾血症的腹膜透析患者中发现CD4+T细胞分化异常。然而尚不清楚LAP过程及CD4+T细胞分化平衡在肠道免疫防御及细菌移位中的作用，两者是否存在关联。假设低钾环境下，LAP受损影响CD4+T细胞分化，共同导致肠道病原菌清除能力下降，引起细菌移位。基于前期研究基础，本项目拟通过动物和细胞实验，探讨LAP对T细胞分化调节在肠道免疫防御及细菌移位中的作用，试图从免疫防御的角度揭示低钾增加肠源性腹膜炎的发病机制，为其防治提供实验依据及干预靶点。

低钾血症是腹膜透析相关性腹膜炎的危险因素。本研究主要探讨低钾对肠道通透性的影响及相关机制。我们的研究结果发现:①低钾饮食可成功构建小鼠低钾血症模型；②低钾血症小鼠存在细菌移位现象；③低钾环境下，炎症因子水平下降；④低钾环境下，经典自噬蛋白表达增加，非经典自噬蛋白表达水平下降。综上所述，低钾引起细菌移位的发生与肠道免疫屏障受损相关。本研究从免疫防御的角度揭示低钾增加肠源性腹膜炎的发病机制，为其防治提供实验依据及干预靶点。