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Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation
Hongxia Z. Imtiyaz, … , Brian Keith, M. Celeste Simon
Hongxia Z. Imtiyaz, … , Brian Keith, M. Celeste Simon
Published July 19, 2010
Citation Information: J Clin Invest. 2010;120(8):2699-2714. https://doi.org/10.1172/JCI39506.
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Research Article Oncology

Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation

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Abstract

Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1α and HIF-2α, and overexpression of HIF-2α in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. We demonstrate here that mice lacking HIF-2α in myeloid cells (Hif2aΔ/Δ mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2aΔ/Δ 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-2α 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-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.

Authors

Hongxia Z. Imtiyaz, Emily P. Williams, Michele M. Hickey, Shetal A. Patel, Amy C. Durham, Li-Jun Yuan, Rachel Hammond, Phyllis A. Gimotty, Brian Keith, M. Celeste Simon

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Figure 8

Loss of TAM HIF-2α leads to reduced tumor burden and progression in murine CAC.

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Loss of TAM HIF-2α leads to reduced tumor burden and progression in muri...
(A and B) Control (Δ/+) and mutant (Δ/Δ) mice were induced to form CAC for 14 weeks, and gross pictures of tumors in the colon and rectum are shown. Arrowheads indicate macroscopic lesions. Scale bars: 3.125 mm. (C and D) Colon sections were stained with H&E; neoplastic lesions are outlined with yellow dashes. Scale bars: 3.125 mm. (E) Top panel shows total number of CAC tumors in both control and mutant cohorts. Bottom panel shows total tumor size (represented as sum of diameters of all tumors). Bars indicate median value of each group. (F) CD68 immunostaining of CAC colons. Left: Distribution of CD68+ macrophages (brown) in normal colon tissue adjacent to tumors. Middle: CD68+ TAM infiltration to the surrounding lamina propria (LP) of hyperplasia. Right: TAM recruitment to LP at stalk area of hyperplasia. Scale bars: 20 μm. (G) CD68 immunostaining of CAC adenomas. Left: Limited TAM infiltration to the center of large lesions. Middle: TAM recruitment to small lesions. Right: TAMs presented in LP at stalk area. Scale bars: 20 μm. (H) Quantification of CD68+ cells. (I) Quantification of tumor stages of CAC. Percentages of hyperplasia and adenoma within control (Δ/+) and mutant (Δ/Δ) groups are shown. (J) Histopathological analysis of mitosis of adenoma tumor cells. Arrowheads in F and G indicate CD68+ TAMs. T, tumor area; S, stalk. *P < 0.05, ***P < 0.001.
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