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J Immunol. 2016 Aug 15;197(4):1287-97. doi: 10.4049/jimmunol.1600266. Epub 2016 Jul 18.

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

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720;
2
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720; and.
3
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
4
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720; and sastanley@berkeley.edu.

Abstract

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. In this study, we show that the transcription factor hypoxia-inducible factor-1α (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-sequencing demonstrates that HIF-1α regulates nearly one-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 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.

PMID:
27430718
PMCID:
PMC4976004
DOI:
10.4049/jimmunol.1600266
[Indexed for MEDLINE]
Free PMC Article

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