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Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein

机译:凋亡细胞的持续清除主要取决于吞噬细胞Ucp2蛋白

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摘要

Rapid and efficient removal of apoptotic cells by phagocytes is important during development, tissue homeostasis and in immune responses~(1-5). Efficient clearance depends on the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the corpse-derived cellular material~6. However, the factors that influence continued clearance by phagocytes are not known. Here we show that the mitochondrial membrane potential of the phagocyte critically controls engulfment capacity, with lower potential enhancing engulfment and vice versa. The mitochondrial membrane protein Ucp2, which acts to lower the mitochondrial membrane potential~(7-9), was upregulated in phagocytes engulfing apoptotic cells. Loss of Ucp2 reduced phagocytic capacity, whereas Ucp2 overexpression enhanced engulfment. Mutational and pharmacological studies indicated a direct role for Ucp2-mediated mitochondrial function in phagocytosis. Macrophages from Ucp2-defident mice1011 were impaired in phagocytosis in vitro, andUcp2-deficient mice showed profound in vivo defects in clearing dying cells in the thymus and testes. Collectively, these data indicate that mitochondrial membrane potential and Ucp2 are key molecular determinants of apoptotic cell clearance. As Ucp2 is linked to metabolic diseases and atherosclerosis~(11,12), this newly discovered role for Ucp2 in apoptotic cell clearance has implications for the complex aetiology and pathogenesis of these diseases.
机译:在发育,组织稳态和免疫应答中,吞噬细胞快速有效地清除凋亡细胞非常重要(1-5)。有效清除取决于单个吞噬细胞连续摄取多个凋亡细胞以及处理尸体来源的细胞物质的能力。但是,尚不知道影响吞噬细胞持续清除的因素。在这里,我们显示吞噬细胞的线粒体膜电位可以严格控制吞噬能力,​​而较低的电位可以增强吞噬能力,​​反之亦然。在吞噬凋亡细胞的吞噬细胞中,线粒体膜蛋白Ucp2降低线粒体膜电位〜(7-9)。 Ucp2的丢失会减少吞噬能力,​​而Ucp2的过表达会增强吞噬作用。突变和药理研究表明,Ucp2介导的线粒体功能在吞噬作用中具有直接作用。 Ucp2缺陷小鼠的巨噬细胞在体外吞噬功能受损,而Ucp2缺陷小鼠在清除胸腺和睾丸中的垂死细胞方面表现出深刻的体内缺陷。总的来说,这些数据表明线粒体膜电位和Ucp2是凋亡细胞清除的关键分子决定因素。由于Ucp2与代谢性疾病和动脉粥样硬化有关,(11,12),这种新发现的Ucp2在凋亡细胞清除中的作用对这些疾病的复杂病因和发病机制具有影响。

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  • 来源
    《Nature》 |2011年第7363期|p.220-224|共5页
  • 作者单位

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA;

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA;

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA;

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA;

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA;

    Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA;

    Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA;

    Department of Urology, University of Virginia, Charlottesville, Virginia 22908, USA;

    Department of Pharmacology and CVRC, University of Virginia, Charlottesville, Virginia 22908, USA;

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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