HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis
In: Journal of immunology (Baltimore, Md. : 1950), Jg. 197 (2016-02-18), Heft 4
Online
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Zugriff:
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.
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HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis
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Autor/in / Beteiligte Person: | Braverman, Jonathan ; Nomura, Daniel K. ; Benjamin, Daniel I. ; Sogi, Kimberly M. ; Stanley, Sarah A. |
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Zeitschrift: | Journal of immunology (Baltimore, Md. : 1950), Jg. 197 (2016-02-18), Heft 4 |
Veröffentlichung: | 2016 |
Medientyp: | unknown |
ISSN: | 1550-6606 (print) |
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