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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress
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Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress

机译：人类单核细胞的碱基和DNA双链断裂修复受到严重损害，使其易遭受氧化应激

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摘要

Monocytes are key players in the immune system. Crossing the blood barrier, they infiltrate tissues and differentiate into (i) mac-rophages that fight off pathogens and (ii) dendritic cells (DCs) that activate the immune response. A hallmark of monocyte/macro-phage activation is the generation of reactive oxygen species (ROS) as a defense against invading microorganisms. How monocytes, macrophages, and DCs in particular respond to ROS is largely unknown. Here we studied the sensitivity of primary human monocytes isolated from peripheral blood and compared them with macrophages and DCs derived from them by cytokine maturation following DNA damage induced by ROS. We show that monocytes are hypersensitive to ROS, undergoing excessive apo-ptosis. These cells exhibited a high yield of ROS-induced DNA single- and double-strand breaks and activation of the ATR-Chk1-ATM-Chk2-p53 pathway that led to Fas and caspase-8, -3, and -7 activation, whereas macrophages and DCs derived from them were protected. Monocytes are also hypersensitive to ionizing radiation and oxidized low-density lipoprotein. The remarkable sensitivity of monocytes to oxidative stress is caused by a lack of expression of the DNA repair proteins XRCC1, ligase IIIα, poly (ADP-ribose) polymerase-1, and catalytic subunit of DNA-depen-dent protein kinase (DNA-PK_(cs)), causing a severe DNA repair defect that impacts base excision repair and double-strand break repair by nonhomologous end-joining. During maturation of monocytes into macrophages and DCs triggered by the cytokines GM-CSF and IL-4, these proteins become up-regulated, making macrophages and DCs repair-competent and ROS-resistant. We propose that impaired DNA repair in monocytes plays a role in the regulation of the monocyte/macrophage/DC system following ROS exposure.
机译：单核细胞是免疫系统的关键参与者。它们穿过血液屏障，渗入组织并分化为（i）抵抗病原体的巨噬细胞和（ii）激活免疫反应的树突状细胞（DC）。单核细胞/巨噬细胞活化的标志是活性氧（ROS）的产生，作为对入侵微生物的防御。单核细胞，巨噬细胞尤其是DC如何对ROS产生反应尚不清楚。在这里，我们研究了从外周血中分离的原代人单核细胞的敏感性，并将其与巨噬细胞和由ROS诱导的DNA损伤后通过细胞因子成熟而从它们衍生的DC进行比较。我们显示，单核细胞对ROS高度敏感，经历了过度的凋亡。这些细胞表现出高产量的ROS诱导的DNA单链和双链断裂以及ATR-Chk1-ATM-Chk2-p53途径的激活，导致Fas和caspase-8，-3和-7激活，而巨噬细胞和衍生自它们的DC受到了保护。单核细胞对电离辐射和氧化的低密度脂蛋白也非常敏感。单核细胞对氧化应激的显着敏感性是由于缺乏DNA修复蛋白XRCC1，连接酶IIIα，聚（ADP-核糖）聚合酶-1和DNA依赖性蛋白激酶（DNA-PK_ （cs）），导致严重的DNA修复缺陷，从而通过非同源末端连接影响碱基切除修复和双链断裂修复。在单核细胞成熟到巨噬细胞和由细胞因子GM-CSF和IL-4触发的DC的过程中，这些蛋白质被上调，使巨噬细胞和DC具有修复能力和ROS抵抗力。我们建议受损的单核细胞DNA修复在ROS暴露后对单核细胞/巨噬细胞/ DC系统的调节中发挥作用。

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