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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 2

HIF-2α is critical for cytokine production and cardiac function in LPS-induced endotoxemia.

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HIF-2α is critical for cytokine production and cardiac function in LPS-i...
(A) Control (Δ/+) and mutant (Δ/Δ) mice were challenged with LPS (15 mg/kg body weight) via i.p. injection; serum was obtained 4 hours following the challenge; and cytokine levels were determined using ELISA. Representative data from 5 mice per group are shown (*P < 0.05, **P < 0.01). (B) Hif2aΔ/Δ animals maintained body temperature better than controls 4 hours following LPS treatment (Hif2aΔ/+, n = 3; Hif2aΔ/Δ, n = 6) (*P < 0.05). (C) Echocardiography showed better LV function in mutant mice 4 hours following LPS treatment (Hif2aΔ/+, n = 3; Hif2aΔ/Δ, n = 6) (*P < 0.05). (D) Mutant mice were pretreated with either anti–IL-10 antibody or isotype control IgG, and their LV function was examined 4 hours following LPS induction of endotoxemia (n = 3) (*P < 0.05). (E) A Kaplan-Meier curve representing survival of animals challenged with LPS (Hif2aΔ/+, n = 7; Hif2aΔ/Δ, n = 6; log-rank statistic = 12.50, P = 0.0004).
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