Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, 230022, Anhui, China.
Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, Guangzhou, China.
Cell Death Dis. 2020 Sep 24;11(9):800. doi: 10.1038/s41419-020-02982-0.
Macrophages are plastic cells that can switch among different states according to bioenergetic or biosynthetic requirements. Our previous work demonstrated that the transcription factor Forkhead Box Protein 1 (FoxO1) plays a pivotal role in regulating the function of macrophages, but the underlying mechanisms are still unclear. Here we identify FoxO1 as a regulator of macrophage function through metabolic reprogramming. Transcriptomic and proteomic analyses showed that the deficiency of FoxO1 results in an alternatively activated (M2) phenotype of macrophages, with lower expression of inflammatory response- and migration-associated genes. Using the high content screening and analysis technology, we found that deletion of FoxO1 in macrophages slows their migration rate and impairs their function to limit tumor cell growth in vitro. Next, we demonstrated that glycolysis is inhibited in FoxO1-deficient macrophages, which leads to the observed functional changes and the reduced tumor suppression capability. This prospective study shows that FoxO1 serves as a bridge between metabolism and macrophage function.
巨噬细胞是具有可塑性的细胞，可以根据生物能量或生物合成的需求在不同状态之间切换。我们之前的工作表明，转录因子叉头框蛋白 1（FoxO1）在调节巨噬细胞的功能方面起着关键作用，但潜在的机制尚不清楚。在这里，我们通过代谢重编程确定 FoxO1 是巨噬细胞功能的调节因子。转录组和蛋白质组分析表明，FoxO1 的缺失导致巨噬细胞呈现出一种替代性激活（M2）表型，炎症反应和迁移相关基因的表达水平降低。使用高通量筛选和分析技术，我们发现巨噬细胞中 FoxO1 的缺失会降低其迁移率并损害其功能，从而在体外限制肿瘤细胞的生长。接下来，我们证明了 FoxO1 缺失的巨噬细胞中的糖酵解受到抑制，这导致了观察到的功能变化和肿瘤抑制能力的降低。这项前瞻性研究表明，FoxO1 是代谢和巨噬细胞功能之间的桥梁。
