We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.
- Authors
Imtiyaz, Hongxia Z.; Williams, Emily P.; Hickey, Michele M.; Patel, Shetal A.; Durham, Amy C.; Li-Jun Yuan; Hammond, Rachel; Gimotty, Phyllis A.; Keith, Brian; Simon, M. Celeste; Yuan, Li-Jun
- Abstract
Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1alpha and HIF-2alpha, and overexpression of HIF-2alpha in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2alpha during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1alpha versus HIF-2alpha must be elucidated. We demonstrate here that mice lacking HIF-2alpha in myeloid cells (Hif2aDelta/Delta mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2alpha directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2aDelta/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-2alpha 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-2alpha as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.
- Subjects
HYPOXEMIA; MACROPHAGES; TUMORS; INFLAMMATION; CANCER; HOMEOSTASIS; CELL receptors; ANIMAL experimentation; BIOLOGICAL models; CELL motility; COMPARATIVE studies; CYTOKINES; IMMUNITY; RESEARCH methodology; MEDICAL cooperation; MICE; NITRIC oxide; PROTEINS; RESEARCH; EVALUATION research; ENDOTOXEMIA; ACUTE diseases; LIPOPOLYSACCHARIDES; PHYSIOLOGY; CELL physiology
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 8, p2699
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI39506