HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury

Abstract

Cellular metabolism is a critical regulator of macrophage effector function. Tissue-resident alveolar macrophages (TR-AMs) inhabit a unique niche marked by high oxygen and low glucose. We have recently shown that in contrast to bone marrow-derived macrophages (BMDMs), TR-AMs do not utilize glycolysis and instead predominantly rely on mitochondrial function for their effector response. It is not known how changes in local oxygen concentration that occur during conditions such as acute respiratory distress syndrome (ARDS) might affect TR-AM metabolism and function; however, ARDS is associated with progressive loss of TR-AMs, which correlates with the severity of disease and mortality. Here, we demonstrate that hypoxia robustly stabilizes HIF-1α in TR-AMs to promote a glycolytic phenotype. Hypoxia altered TR-AM metabolite signatures, cytokine production, and decreased their sensitivity to the inhibition of mitochondrial function. By contrast, hypoxia had minimal effects on BMDM metabolism. The effects of hypoxia on TR-AMs were mimicked by FG-4592, a HIF-1α stabilizer. Treatment with FG-4592 decreased TR-AM death and attenuated acute lung injury in mice. These findings reveal the importance of microenvironment in determining macrophage metabolic phenotype, and highlight the therapeutic potential in targeting cellular metabolism to improve outcomes in diseases characterized by acute inflammation.

Data availability

Source Data files have been provided for Figures 2C, and 5B, C.

Article and author information

Author details

  1. Parker S Woods

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    Parker S Woods, has a pending patent on targeting tissue-resident alveolar macrophage metabolism to prevent their death during ARDS. (ARCD.P0740US.P1/1001176943).
  2. Lucas M Kimmig

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  3. Kaitlyn A Sun

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  4. Angelo Y Meliton

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  5. Obada R Shamaa

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  6. Yufeng Tian

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  7. Rengül Cetin-Atalay

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  8. Willard W Sharp

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  9. Robert B Hamanaka

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    Robert B Hamanaka, has a pending patent on targeting tissue-resident alveolar macrophage metabolism to prevent their death during ARDS. (ARCD.P0740US.P1/1001176943).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8909-356X
  10. Gökhan M Mutlu

    Department of Medicine, University of Chicago, Chicago, United States
    For correspondence
    gmutlu@medicine.bsd.uchicago.edu
    Competing interests
    Gökhan M Mutlu, has a pending patent on targeting tissue-resident alveolar macrophage metabolism to prevent their death during ARDS. (ARCD.P0740US.P1/1001176943).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2056-612X

Funding

U.S. Department of Defense (W81XWH-16-1-0711)

  • Gökhan M Mutlu

National Institute of Environmental Health Sciences (R01ES010524)

  • Gökhan M Mutlu

National Heart, Lung, and Blood Institute (R01HL151680)

  • Robert B Hamanaka

National Institute of Environmental Health Sciences (U01ES026718)

  • Gökhan M Mutlu

National Heart, Lung, and Blood Institute (P01HL144454)

  • Gökhan M Mutlu

National Heart, Lung, and Blood Institute (T32HL007605)

  • Parker S Woods
  • Lucas M Kimmig
  • Obada R Shamaa
  • Gökhan M Mutlu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

Ethics

Animal experimentation: All animal experiments and procedures were performed according to the protocols (ACUP7236 and ACUP72484) approved by the Institutional Animal Care and Use Committee at the University of Chicago.

Version history

  1. Received: January 31, 2022
  2. Preprint posted: March 1, 2022 (view preprint)
  3. Accepted: July 10, 2022
  4. Accepted Manuscript published: July 13, 2022 (version 1)
  5. Version of Record published: July 26, 2022 (version 2)

Copyright

© 2022, Woods et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Parker S Woods
  2. Lucas M Kimmig
  3. Kaitlyn A Sun
  4. Angelo Y Meliton
  5. Obada R Shamaa
  6. Yufeng Tian
  7. Rengül Cetin-Atalay
  8. Willard W Sharp
  9. Robert B Hamanaka
  10. Gökhan M Mutlu
(2022)
HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury
eLife 11:e77457.
https://doi.org/10.7554/eLife.77457

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https://doi.org/10.7554/eLife.77457

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