ANGPTL4基于糖脂代谢调控对CD8+T和巨噬细胞活性的影响及其机制

Angiopoietin-like 4 (ANGPTL4), as an important member of angiopoietin-like protein family, regulates the glycolipid metabolism and is associated with the development of inflammation and tumor. Our study group previously found that frequencies and activities of CD8+ T cells and M1 macrophages in spleens of ANGPTL4-/- mice were significantly increased. Meanwhile, Glut1 and HK II of the key glycolysis molecules were higher expressed in CD8+ T cells of ANGPTL4-/- mice. However, whether ANGPTL4 can directly affect the function of CD8+ T cells and macrophages through regulating glycolipid metabolism remains further detailed study. Firstly, this project is to determine whether ANGPTL4 can directly regulate the function of CD8+ T cells and macrophages based on the ANGPTL4-/- mice and the stimulation of recombinant ANGPTL4 protein. Then we observe how ANGPTL4 changes the glycolipid metabolism of CD8+ T cells and macrophages and thus affects the function of two immune cells. Whether functional variations of CD8+ T cells and macrophages regulated by ANGPTL4 are involved in inflammation is also analyzed. Finally, molecular mechanisms of metabolic reprogramming in CD8+ T cells and macrophages induced by ANGPTL4 are investigated. The completion of this project will provide an important strategy for development of the ANGPTL4-based biological agents for interfering inflammation.

ANGPTL4作为血管生成素样蛋白家族重要成员之一，具有调节糖脂代谢活性，与炎症和肿瘤发病有关。课题组通过引进ANGPTL4-/-小鼠，发现该小鼠脾脏CD8+T和M1型巨噬细胞的频率和活性均明显升高，且CD8+T细胞糖酵解关键分子Glut1和HKII表达上调。然而，ANGPTL4是否通过调节糖脂代谢而直接影响CD8+T和巨噬细胞功能的作用及机制期待深入研究。本项目首先基于ANGPTL4-/-小鼠和重组ANGPTL4蛋白刺激，明确ANGPTL4可否直接调节CD8+T和巨噬细胞的功能；然后观察ANGPTL4如何改变CD8+T和巨噬细胞的糖脂代谢方式而影响两种免疫细胞功能；并分析ANGPTL4调控的CD8+T和巨噬细胞活性改变是否参与炎症过程；最后深入探讨ANGPTL4调控CD8+T和巨噬细胞发生代谢重塑的分子机制。本项目的完成将为研发基于ANGPTL4的生物制剂用于炎症干预提供重要策略。

ANGPTL4作为一种分泌型代谢调节糖蛋白，其在巨噬细胞和CD8+T细胞的代谢作用机制，目前尚不清楚。.本项目基于ANGPTL4-/-小鼠和ANGPTL4重组蛋白刺激，明确ANGPTL4是否引起代谢方式的改变影响CD8+T和巨噬细胞的功能，探讨该调节作用在炎症性肠病和结直肠癌的意义，阐明其潜在相关分子机制。.结果显示ANGPTL4缺失可促进CD8+T和巨噬细胞的产生，外源性给予rANGPTL4可抑制CD8+T细胞的活性，对巨噬细胞无明显影响；巨噬细胞中ANGPTL4缺失可诱导胞内脂肪酸代谢重编程，引起内质网应激和炎症反应；ANGPTL4缺失通过代谢重编程增强CD8+T细胞的活性从而延缓肿瘤进展，其机制依赖于PKC-LKB1-AMPK-mTOR信号轴的调控；增加ANGPTL4可抑制CD8+T细胞活性，从而改善炎症性肠病。.本研究揭示在肿瘤微环境或肠道炎症状态下，CD8+T/巨噬细胞内ANGPTL4的表达发生动态变化，引起代谢重编程，从而调节CD8+T/巨噬细胞的生物学活性。提示干预ANGPTL4的分泌可用于治疗结直肠癌和炎症性肠病。