基于AMPK调节mTORC1/mTORC2信号探讨薯蓣皂苷影响巨噬细胞极化和治疗UC的机制

溃疡性结肠炎（UC）被WHO列为现代难治病之一。巨噬细胞（Mφ）表型受代谢机制的严格调控，其主导的肠道免疫调节失衡在UC发病中至关重要。抑制UC病人结肠Mφ向促炎的M1极化，促进其向抑炎的M2极化能显著缓解UC。因而，靶向调节Mφ代谢过程和免疫活性是UC治疗新靶点。前期发现，薯蓣皂苷能缓解DSS小鼠UC，其机制可能与激活Mφ的能量调节关键激酶AMPK，抑制mTORC1/HIF-1α/有氧糖酵解和M1极化，但促进mTORC2/PPAR-γ/脂肪酸氧化和M2极化有关。课题组提出“薯蓣皂苷可能作用于AMPK-mTORC1/mTORC2信号，调控Mφ代谢途径和极化表型，抑制Mφ炎性反应，治疗UC”的假说。拟采用基因沉默等手段，借助工具药，从动物及细胞模型研究薯蓣皂苷对AMPK及下游通路的影响，查明其调节Mφ表型，缓解UC炎性反应的机制；为靶向调控免疫细胞代谢和表型，治疗免疫炎性疾病提供实验依据。

Ulcerative colitis (UC) is listed as one of the modern refractory diseases by WHO. Imbalanced intestinal immune regulation driven by macrophages (Mφ) is a crucial trigger in the pathogenesis of UC, and the phenotypes of Mφ are strictly regulated by metabolic mechanisms. Studies showed that inhibiting the polarization of Mφ to pro-inflammatory M1, while skewing their polarization to anti-inflammatory M2 can effectively alleviate UC. Therefore, targeted regulation of Mφ metabolic processes and immune activity is a new strategy for UC therapy. Our previous data showed that Dioscin evidently ameliorated DSS-induced mice UC, which mechanism most likely mediated by activating Mφ AMPK, the key kinase sensing intracellular energy fluctuation and regulating energy metabolism. Dioscin inhibited aerobic glycolysis mediated by mTORC1/HIF-1α signal, and restrained polarization of Mφ to M1; but promoted fatty acid oxidation modulated by mTORC2/PPAR-γ, and skewed polarization of Mφ to M2. Based on these facts, it can be speculated that “Dioscin probably regulate mTORC1/mTORC2 signals by activating AMPK, intervene Mφ metabolic reprogramming, adjusting Mφ phenotype, and by this way inhibit Mφ pro-inflammatory response to relieve UC”. This project aims to investigate the therapeutic mechanism of Dioscin on mice colitis by focusing on its’ regulation on Mφ phenotypes and metabolic pathways. A series of studies would be carried out on DSS mice and Mφ polarization models, with the aid of techniques including small interfering RNA, kinase inhibitors, and AMPKα1 gene knout on mice. The results may provide experimental evidence supporting the recent therapeutic strategy that is to ameliorate autoimmune and inflammatory diseases by targeted metabolic regulation of immunocytes.