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

HZ Imtiyaz, EP Williams, MM Hickey… - The Journal of …, 2010 - Am Soc Clin Investig
HZ Imtiyaz, EP Williams, MM Hickey, SA Patel, AC Durham, LJ Yuan, R Hammond…
The Journal of clinical investigation, 2010Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation