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

• Published in: The Journal of clinical investigation 2010-08, Vol.120 (8), p.2699-2714
• Main Authors: Imtiyaz, Hongxia Z, Williams, Emily P, Hickey, Michele M, Patel, Shetal A, Durham, Amy C, Yuan, Li-Jun, Hammond, Rachel, Gimotty, Phyllis A, Keith, Brian, Simon, M. Celeste
• Format: Article
• Language: English
• Subjects: Care and treatment; Development and progression; Genetic aspects; Genetic regulation; Hypoxia; Inflammation; Macrophages
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI39506

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 ([Hif2a.sup.Δ/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. [Hif2a.sup.Δ/Δ] mice displayed reduced TAM infiltration in independent murine hepatocellular and colitisassociated 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.