Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.
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.
Imtiyaz
Hongxia Z
HZ
Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA
Williams
Emily P
EP
Hickey
Michele M
MM
Patel
Shetal A
SA
Durham
Amy C
AC
Yuan
Li-Jun
LJ
Hammond
Rachel
R
Gimotty
Phyllis A
PA
Keith
Brian
B
Simon
M Celeste
MC
D000208:Acute Disease; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D019718:Receptors, CXCR4; D000099162:Endothelial PAS Domain-Containing Protein 1; C514936:CXCR4 protein, mouse