HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis.
HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis.
复制标题
DOI：
10.4049/jimmunol.1600266
复制
发表时间：
2016-08-15
期刊：
影响因子：
--
通讯作者：
Stanley SA
中科院分区：
文献类型：
--
作者：
Braverman J;Sogi KM;Benjamin D;Nomura DK;Stanley SA
细胞因子IFN-γ协调巨噬细胞活化，并且对于控制包括结核分枝杆菌在内的病原体是必需的。然而，IFN-γ控制M.结核病的感染只是部分了解。在此，我们发现转录因子HIF-1α是IFN-γ依赖性M.结核感染的体外和体内。M.结核感染IFN-γ激活的巨噬细胞导致HIF-1α蛋白水平的协同增加。HIF-1α水平的这种增加在功能上是重要的，因为缺乏HIF-1α的巨噬细胞对于IFN-γ依赖性感染控制是有缺陷的。RNA-seq分析表明，在巨噬细胞感染期间，HIF-1α调节近一半的IFN-γ诱导基因。特别是，HIF-1α调节重要的免疫效应物的产生，包括炎性细胞因子和趋化因子、类花生酸和一氧化氮（NO）。此外，我们发现在感染过程中，HIF-1α协调IFN-γ激活的巨噬细胞中有氧糖酵解的代谢转变。我们发现这种增强的糖酵解通量对于IFN-γ依赖性控制巨噬细胞中的感染至关重要。此外，我们确定了HIF-1α和有氧糖酵解之间的正反馈回路，该回路放大了巨噬细胞的活化。最后，我们证明了HIF-1α对于体内感染的控制至关重要，因为骨髓谱系中缺乏HIF-1α的小鼠对感染非常敏感，并且表现出炎症细胞因子和杀微生物效应物的缺陷。总之，我们已经确定HIF-1α是一种新的IFN-γ依赖性免疫调节因子，它协调了控制M.结核感染的体外和体内研究。
The cytokine IFN-γ coordinates macrophage activation and is essential for control of pathogens including Mycobacterium tuberculosis. However, the mechanisms by which IFN-γ controls M. tuberculosis infection are only partially understood. Here, we show that the transcription factor HIF-1α is an essential mediator of IFN-γ dependent control of M. tuberculosis infection both in vitro and in vivo. M. tuberculosis infection of IFN-γ activated macrophages results in a synergistic increase in HIF-1α protein levels. This increase in HIF-1α levels is functionally important, as macrophages lacking HIF-1α are defective for IFN-γ dependent control of infection. RNA-seq profiling demonstrates that HIF-1α regulates nearly half of all IFN-γ inducible genes during infection of macrophages. In particular, HIF-1α regulates production of important immune effectors including inflammatory cytokines and chemokines, eicosanoids, and nitric oxide (NO). In addition, we find that during infection HIF-1α coordinates a metabolic shift to aerobic glycolysis in IFN-γ activated macrophages. We find that this enhanced glycolytic flux is crucial for IFN-γ dependent control of infection in macrophages. Furthermore, we identify a positive feedback loop between HIF-1α and aerobic glycolysis that amplifies macrophage activation. Finally, we demonstrate that HIF-1α is crucial for control of infection in vivo as mice lacking HIF-1α in the myeloid lineage are strikingly susceptible to infection, and exhibit defective production of inflammatory cytokines and microbicidal effectors. In conclusion, we have identified HIF-1α as a novel regulator of IFN-γ dependent immunity that coordinates an immunometabolic program essential for control of M. tuberculosis infection in vitro and in vivo.