HIF-1? Is an Essential Mediator of IFN-?-Dependent Immunity to Mycobacterium tuberculosis.

ABSTRACT: The cytokine IFN-? coordinates macrophage activation and is essential for control of pathogens, including Mycobacterium tuberculosis However, the mechanisms by which IFN-? controls M. tuberculosis infection are only partially understood. In this study, we show that the transcription factor hypoxia-inducible factor-1? (HIF-1?) is an essential mediator of IFN-?-dependent control of M. tuberculosis infection both in vitro and in vivo. M. tuberculosis infection of IFN-?-activated macrophages results in a synergistic increase in HIF-1? protein levels. This increase in HIF-1? levels is functionally important, as macrophages lacking HIF-1? are defective for IFN-?-dependent control of infection. RNA-sequencing demonstrates that HIF-1? regulates nearly one-half of all IFN-?-inducible genes during infection of macrophages. In particular, HIF-1? regulates production of important immune effectors, including inflammatory cytokines and chemokines, eicosanoids, and NO. In addition, we find that during infection HIF-1? coordinates a metabolic shift to aerobic glycolysis in IFN-?-activated macrophages. We find that this enhanced glycolytic flux is crucial for IFN-?-dependent control of infection in macrophages. Furthermore, we identify a positive feedback loop between HIF-1? and aerobic glycolysis that amplifies macrophage activation. Finally, we demonstrate that HIF-1? is crucial for control of infection in vivo as mice lacking HIF-1? 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-1? as a novel regulator of IFN-?-dependent immunity that coordinates an immunometabolic program essential for control of M. tuberculosis infection in vitro and in vivo.

SUBMITTER: Braverman J 

PROVIDER: S-EPMC4976004 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature