Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation
Open accessAbstract
Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1alpha and HIF-2alpha, and overexpression of HIF-2alpha in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2alpha during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1alpha versus HIF-2alpha must be elucidated. We demonstrate here that mice lacking HIF-2alpha in myeloid cells (Hif2aDelta/Delta mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2alpha directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2aDelta/Delta mice displayed reduced TAM infiltration in independent murine hepatocellular and colitis-associated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2alpha modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2alpha as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.
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Myeloid-specific HIF-1α deletion causes defective glycolysis and ATP generation, impairing myeloid cell motility and function.
“Myeloid-specific HIF-1α deletion results in defective glycolysis and ATP generation, leading to impairment of myeloid cell motility and function (Fig. 2B) [61,62].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [62]
The migration-and-invasion section reports ATP depletion in HIF-1α-deficient macrophages, and the discussion reports reduced migration, inflammation, and bacterial killing after macrophage HIF-1α loss. It also cites a role for HIF-1α in glycolysis in hypoxic cells. But the discussion explicitly says it is unclear how much of the functional impairment results from reduced ATP, so the claim’s causal link is stronger than this source supports. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHIF-1α or HIF-2α expression in TAMs is associated with tumor progression and/or poor prognosis in multiple tumor types.
“Both HIF-1α or HIF-2α expression in TAMs have been associated with tumor progression and/or poor prognosis in multiple tumor types, whereas lack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6 [73–76].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [76]
The Figure 10 passage reports that high HIF-2α levels in TAMs correlate with increased tumor grade and vascularity, and that more HIF-2α-expressing TAMs are associated with poor prognosis. The Discussion says HIF-2α is found in TAMs across various human cancers, but it does not establish the claimed association for HIF-1α expression in TAMs. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6.
“Both HIF-1α or HIF-2α expression in TAMs have been associated with tumor progression and/or poor prognosis in multiple tumor types, whereas lack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6 [73–76].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [76]
The tumor-progression section reports reduced tumor-cell mitosis and compromised progression after myeloid HIF-2α deletion. The cytokine section reports reduced IL-6 secretion from activated HIF-2α-deficient macrophages in vitro, but IL-6 reduction in the tumors is proposed as a possible explanation, not established. The paper does not report reduced metastasis or test HIF-1α deletion in these tumor models; it proposes the latter as future work. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTAM presence and number directly correlate with prognosis in several cancer types and model systems.
“Indeed, TAM presence and number has been directly correlated with prognosis in a number of cancer types and model systems [42–44].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [42]
Macrophages need HIF2α for cytokine induction.
“HIF2α is required for cytokine induction in macrophages (Imtiyaz et al., 2010).”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Imtiyaz et al., 2010
Hif-2α is an important transcriptional regulator of hypoxic responses, controlling processes including hypoxic regulation of EPO synthesis and macrophage function.
“Hif-2α is an important transcriptional regulator of hypoxic responses, controlling a variety of processes including hypoxic regulation of EPO synthesis [48, 49] and macrophage function [50, 51].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [51]
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- Authors
- Imtiyaz, H. Z., Williams, E. P., Hickey, M. M., Patel, S. A., Durham, A. C., Yuan, L.-J., Hammond, R., Gimotty, P. A., Keith, B., & Simon, M. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Abramson Cancer Center (US)
- Corresponding author
- Simon, M. Celeste
- Venue
- Journal of Clinical Investigation
- Published
- 2010-08-02
- Volume
- 120
- Issue
- 8
- Pages
- 2699-2714
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2912179
- OpenAlex
- W2041418689
- Semantic Scholar
- f822a56ab9aa8dcad2e6f306df8394ee6666f231
- Cited by
- 461
- References
- 116
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 22 · 2023: 26 · 2022: 38 · 2021: 45 · 2020: 33 · 2019: 27 · 2018: 29 · 2017: 18 · 2016: 32 · 2015: 23 · 2014: 36 · 2013: 29 · 2012: 32
- FWCI
- 12.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- National Institutes of Health
- Directorate for Biological Sciences
- U.S. Public Health Service (66310)
- Abramson Family Cancer Research Institute
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Keywords
- HIF-2α, HIF-1α, tumor-associated macrophages, macrophage function, hypoxia, innate immunity, endotoxemia, lipopolysaccharide, inflammatory cytokines, chemokines, macrophage migration, M-CSF receptor, CXCR4, hepatocellular carcinoma, tumor inflammation, myeloid-specific knockout
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Acute Disease, Animals, Cell Movement, Disease Models, Animal, Female, Immunity, Innate, Inflammation, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Neoplasms, Nitric Oxide, Cytokines, Endotoxemia, Receptors, CXCR4, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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