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

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 1

Myeloid-specific ablation of HIF-2α using LysM-Cre.

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Myeloid-specific ablation of HIF-2α using LysM-Cre. (A) Breeding scheme ...
(A) Breeding scheme used to obtain myeloid-specific HIF-2α–deficient (Hif2aΔ/Δ, i.e., Hif2a2L/1L, LysM-Cre) and control (Hif2aΔ/+, i.e., Hif2a2L/+, LysM-Cre) mice. 2L, 2loxP allele; 1L, 1loxP or deleted allele. Frequency of each genotype is shown. (B) Southern blot showing deletion of the 2loxP allele in macrophages (M). Tail tissue (T) was used as a control. (C) Western blots confirming the absence of HIF-2α protein under hypoxia in Hif-2αΔ/Δ BMDMs. (D) HIF target expression validating loss of HIF-2α function in HIF-2α–deficient BMDMs. Data represent fold induction of mRNA expression compared with the control BMDMs. Representative data from 4 independent experiments are shown (**P < 0.01). (E) Cytokine/chemokine expression in normoxic and hypoxic BMDMs was evaluated by QRT-PCR. Representative data from at least 3 independent experiments are shown (*P < 0.05, **P < 0.01). Δ/+, control genotype, Hif2aΔ/+; Δ/Δ, mutant genotype, Hif2aΔ/Δ; N, normoxia (21% O2); H, hypoxia (0.5% O2); n.s., nonspecific band.