HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury
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Curated by eLife
Evaluation Summary:
This study provides important new information regarding the functions and behavior of lung tissue-resident alveolar macrophages in the context of acute lung injury. New data regarding the impact of hypoxia via HIF-1 on biology of these critical cells are provided and importantly suggesting an impact on the outcome of lung injury.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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.
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Evaluation Summary:
This study provides important new information regarding the functions and behavior of lung tissue-resident alveolar macrophages in the context of acute lung injury. New data regarding the impact of hypoxia via HIF-1 on biology of these critical cells are provided and importantly suggesting an impact on the outcome of lung injury.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
This work adds to an already abundant literature demonstrating that TR-AMs are a phenotypically and functionally distinct population of macrophages. Work in this manuscript is the first to characterize the effect of hypoxia on metabolic and inflammatory responses in TR-AMs vs macrophages derived from other sites (bone marrow).
Strengths:
1. Findings advance our understanding of TR-AM biology and further highlight the unique characteristics of this macrophage subset.
2. Studies suggest that morbidity and mortality from pneumonia and other causes of acute lung injury may depend on the ability of TR-AMs to metabolically adapt to hypoxic conditions.
3. Studies suggest that targeting cellular metabolism may be effective in treating hypoxic respiratory conditions.Weaknesses:
1. Study conclusions are largely …Reviewer #1 (Public Review):
This work adds to an already abundant literature demonstrating that TR-AMs are a phenotypically and functionally distinct population of macrophages. Work in this manuscript is the first to characterize the effect of hypoxia on metabolic and inflammatory responses in TR-AMs vs macrophages derived from other sites (bone marrow).
Strengths:
1. Findings advance our understanding of TR-AM biology and further highlight the unique characteristics of this macrophage subset.
2. Studies suggest that morbidity and mortality from pneumonia and other causes of acute lung injury may depend on the ability of TR-AMs to metabolically adapt to hypoxic conditions.
3. Studies suggest that targeting cellular metabolism may be effective in treating hypoxic respiratory conditions.Weaknesses:
1. Study conclusions are largely dependent on the use of non-selective pharmacological inhibitors for manipulating HIF-1 signaling, which is particularly true for the compound echinomycin.
2. Intratracheal delivery of FG-4592 will have effects on many cell types in the lung, including other leukocyte populations and may even impact viral proliferation, making it hard to judge whether endpoints are due to direct or indirect effects on TR-AMs.
3. Findings suggest that very low oxygen concentrations contribute to elevated HIF1 signaling and glycolysis in TR-AMs but further justification is needed for the oxygen concentrations used in this study since they seem a bit low for the alveolar environment. Relevant to this, it would be helpful to know whether hypoxia is a feature of the influenza mouse model. -
Reviewer #2 (Public Review):
The manuscript studies how hypoxia impacts tissue-resident macrophage function and response upon influenza infection and lung injury. The authors , in culture studies, first determine an interesting differential response between BMDM and TRAM, such that TRAM was highly responsive to hypoxia. These cells have the ability to stabilize HIF and induce a glycolytic phenotype. The authors mimicked these effects using a pharmacologic activator of HIF. Interestingly, HIF activation was sufficient to decrease TRAM death and attenuated lung injury in mice.
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