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

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and HIF-2 alpha display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIP-la and HIF-2a, and overexpression of HIF-2 alpha in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2 alpha during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1 alpha versus HIF-2 alpha must be elucidated. We demonstrate here that mice lacking HIF-2 alpha in myeloid cells (Hif2a(Delta/Delta) mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2 alpha directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2a(Delta/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-2 alpha 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-2 alpha as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.