mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1α-dependent glycolytic pathway
mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1α-dependent glycolytic pathway
复制标题
DOI：
10.1189/jlb.2a1115-492r
复制
发表时间：
2016-12-01
影响因子：
5.5
通讯作者：
Liu, Guangwei
中科院分区：
文献类型：
--
作者：
Chen, Xi;Zhang, Zhengguo;Liu, Guangwei
雷帕霉素（mTOR）途径的机制靶点整合了多种环境输入，包括免疫信号和代谢线索，以指导先天性和适应性免疫反应。骨髓源性抑制细胞（MDSC）是一种异质细胞群，在免疫相关疾病中发挥着至关重要的调节作用。然而，mTOR 信号传导是否影响 MDSC 的功能仍有待进一步探索。在这里，我们证明 mTOR 信号传导是免疫介导的肝损伤 (IMH) 疾病中 MDSC 功能的关键负向决定因素。在IMH的情况下，用雷帕霉素或mTOR缺陷的CD11b(+)Gr1(+) MDSCs阻断mTOR可介导针对IMH的保护； mTOR 与雷帕霉素和 mTOR 缺陷的 CD11b(+)Gr1(+) MDSC 是抑制性免疫调节剂，导致产生 IFN-gamma 的 T(H)1 细胞减少，而 Foxp3(+) T-reg 细胞增加。从机制上讲，MDSC 中 mTOR 活性下调诱导 iNOS 表达和 NO 产生。 iNOS 的药理学抑制完全消除 MDSC 抑制功能并失去其对 T 细胞分化的诱导作用。重要的是，HIF1 αα依赖性糖酵解活性是导致 IMH 炎症中 mTOR 缺陷、MDSC 功能变化增加的原因。因此，这些数据表明，mTOR 在 MDSC 中充当基本的“变阻器”，将免疫信号与糖酵解途径和功能适应性联系起来，并强调了 MDSC 抑制活性的代谢编程在预防免疫性肝损伤中的核心作用。
The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct innate and adaptive immune responses. Myeloid-derived suppressive cells (MDSCs) are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unexplored. Here, we show that mTOR signaling is a pivotal, negative determinant of MDSC function in immune-mediated hepatic injury (IMH) diseases. In the context of IMH, the blocking of mTOR with rapamycin or mTOR-deficient CD11b(+)Gr1(+) MDSCs mediates the protection against IMH; mTOR with rapamycin and mTOR-deficient CD11b(+)Gr1(+) MDSCs are suppressive immune modulators that result in less IFN-gamma-producing T(H)1 cells and more Foxp3(+) T-regs. Mechanistically, mTOR activity down-regulation in MDSCs induced iNOS expressions and NO productions. Pharmacologic inhibitions of iNOS completely eliminate MDSC-suppressive function and lose their inducible effects on T cell differentiation. Importantly, HIF1 alpha a-dependent glycolytic activity is responsible for mTOR-deficient, increasedMDSC functional changes in IMH inflammation. Thus, these data demonstrate that mTOR acts as a fundamental "rheostat" in MDSCs to link immunologic signals to glycolytic pathways and functional fitness and highlights a central role of metabolic programming of MDSC-suppressive activity in protecting against immune hepatic injuries.