Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor
Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor
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DOI：
10.4049/jimmunol.0801710
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发表时间：
2009-03-01
影响因子：
4.4
通讯作者：
Landazuri, Manuel O.
中科院分区：
文献类型：
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作者：
Acosta-Iborra, Barbara;Elorza, Ainara;Landazuri, Manuel O.
在炎症或病变组织中发现低氧张力区，其中缺氧细胞通过调节缺氧诱导转录因子（HIF）诱导生存途径。巨噬细胞是炎症的重要调节因子，因此，我们分析了它们对缺氧的反应。缺氧条件下培养的海洋腹腔巨噬细胞产生的ifn - γ和IL-12 mRNA和蛋白水平高于正常缺氧条件下培养的巨噬细胞。使用暴露于大气缺氧的小鼠巨噬细胞的体内模型获得了类似的ifn - γ增加。我们的研究表明，ifn - γ的诱导是通过HIF-1 α结合其启动子介导的，该启动子是一个新的功能性缺氧反应元件。hif - α在ifn - γ诱导中的需求在RAW264.7细胞中得到证实，其中HIF-1 α被敲低，以及在常驻的HIF-1 α缺失的巨噬细胞中。此外，低氧条件下，Ag递呈能力通过上调共刺激和Ag递呈受体的表达而增强。低氧巨噬细胞与CD8 T细胞产生生产性免疫突触，更有效地激活TCR/CD3 epsilon， CD3 zeta抗连接子，激活T细胞磷酸化，以及T细胞细胞因子的产生。此外，缺氧巨噬细胞通过上调吞噬受体的表达，以更高的效率结合调理颗粒，增加其吞噬摄取。这些缺氧增加的免疫反应在HIF-1 α和ifn - γ沉默的巨噬细胞中明显减少，表明HIF-1 α和ifn - γ在巨噬细胞对缺氧的功能反应中存在联系。我们的数据强调了缺氧在巨噬细胞细胞因子产生、ag呈递活性和吞噬活性激活中的重要作用，这是由于HIF-1 α介导的ifn - γ水平升高。免疫学杂志，2009,32(2):355 - 364。
Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Marine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-gamma and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN-gamma increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN-gamma induction was mediated through HIF-1 alpha binding to its promoter on a new functional hypoxia response element. The requirement of HIF-alpha in the IFN-gamma induction was confirmed in RAW264.7 cells, where HIF-1 alpha was knocked down, as well as in resident HIF-1 alpha null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3 epsilon, CD3 zeta anti linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1 alpha- and in IFN-gamma-silenced macrophages, indicating a link between HIF-1 alpha and IFN-gamma in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1 alpha-mediated increase in IFN-gamma levels. The Journal of Immunology, 2009, 182: 3155-3164.