Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation
Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation
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DOI：
10.1172/jci39506
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发表时间：
2010-08-01
影响因子：
15.9
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
--
作者：
Imtiyaz, Hongxia Z.;Williams, Emily P.;Simon, M. Celeste
缺氧诱导因子1 α（HIF-1 α）和HIF-2 α在调节细胞能量稳态、细胞命运决定和肿瘤发生中显示独特的且有时相反的活性。暴露于缺氧的巨噬细胞积累HIP-Ia和HIF-2a，并且肿瘤相关巨噬细胞（TAM）中HIF-2 α的过表达与高级别人类肿瘤和不良预后特别相关。然而，HIF-2 α在巨噬细胞介导的炎症反应中的确切作用仍不清楚。为了充分表征细胞缺氧适应，必须阐明HIF-1 α与HIF-2 α的不同功能。我们在这里证明，骨髓细胞中缺乏HIF-2 α的小鼠（Hif 2a（Delta/Delta）小鼠）对脂多糖诱导的内毒素血症具有抵抗力，并显示出对皮肤和腹膜刺激物的炎症反应明显无能。此外，HIF-2 α直接调节体外激活的巨噬细胞中的促炎细胞因子/趋化因子表达。Hif 2a（Delta/Delta）小鼠在独立的小鼠肝细胞和结肠炎相关结肠癌模型中显示TAM浸润减少，这与肿瘤细胞增殖和进展减少有关。值得注意的是，HIF-2 α通过调节细胞因子受体M-CSFR和趋化因子受体CXCR 4的表达来调节巨噬细胞迁移，而不改变细胞内ATP水平。总的来说，我们的数据确定HIF-2 α是先天免疫的重要调节因子，这表明它可能是治疗炎症性疾病和癌症的有用治疗靶点。
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.