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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 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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
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“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
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“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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Metadata
- 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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