Mitochondrial DNA released by trauma induces neutrophil extracellular traps.
Mitochondrial DNA released by trauma induces neutrophil extracellular traps.
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DOI：
10.1371/journal.pone.0120549
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hauser CJ
中科院分区：
文献类型：
--
作者：
Itagaki K;Kaczmarek E;Lee YT;Tang IT;Isal B;Adibnia Y;Sandler N;Grimm MJ;Segal BH;Otterbein LE;Hauser CJ
中性粒细胞胞外陷阱（NET）对于先天免疫系统的抗菌活性至关重要。我们之前已经证明，线粒体损伤相关分子模式 (mtDAMP)，包括线粒体 DNA (mtDNA)，在损伤后释放到循环中。因此，我们质疑 mtDNA 是否参与了创伤诱导的 NET 形成。用 mtDNA 处理人多形中性粒细胞 (PMN) 会诱导强大的 NET 形成，但与佛波醇肉豆蔻酸酯乙酸酯 (PMA) 刺激相反，不需要 NADPH 氧化酶的参与。此外，mtDNA 诱导的 NET 的形成被 TLR9 拮抗剂 ODN-TTAGGG 完全阻断。我们知道老年人创伤的感染后果比年轻人更严重，因此我们测量了老年和年轻创伤患者以及对照受试者的血浆 mtDNA 和 NET 形成。尽管老年创伤患者的损伤严重程度评分较低，但老年创伤患者血浆中的线粒体DNA水平显着高于年轻患者。在从年轻或年老对照受试者中分离出的循环 PMN 中不可见 NET。然而，在年轻创伤患者和老年患者中分离出的 PMN 中检测到了 NET。 PMA 的刺激诱导年轻志愿者和年轻创伤患者的 PMN 中广泛形成 NET。在老年志愿者的 PMN 和创伤患者的 PMN 中，NET 对 PMA 的反应都不那么明显。我们得出结论，mtDNA 是 NET 的有效诱导剂，可通过 TLR9 激活 PMN，而无需 NADPH 氧化酶参与。我们认为，尽管老年人血浆中 mtDNA 水平较高，但 NET 形成减少可能是由于 TLR9 和/或其他分子水平降低所致，例如参与 NET 生成的中性粒细胞弹性蛋白酶和髓过氧化物酶。对循环 mtDNA 和 NET 形成之间联系的进一步研究可能会阐明创伤相关器官衰竭的机制以及老年创伤患者更容易继发感染。
Neutrophil extracellular traps (NETs) are critical for anti-bacterial activity of the innate immune system. We have previously shown that mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA (mtDNA), are released into the circulation after injury. We therefore questioned whether mtDNA is involved in trauma-induced NET formation. Treatment of human polymorphoneutrophils (PMN) with mtDNA induced robust NET formation, though in contrast to phorbol myristate acetate (PMA) stimulation, no NADPH-oxidase involvement was required. Moreover, formation of mtDNA-induced NETs was completely blocked by TLR9 antagonist, ODN-TTAGGG. Knowing that infective outcomes of trauma in elderly people are more severe than in young people, we measured plasma mtDNA and NET formation in elderly and young trauma patients and control subjects. MtDNA levels were significantly higher in the plasma of elderly trauma patients than young patients, despite lower injury severity scores in the elderly group. NETs were not visible in circulating PMN isolated from either young or old control subjects. NETs were however, detected in PMN isolated from young trauma patients and to a lesser extent from elderly patients. Stimulation by PMA induced widespread NET formation in PMN from both young volunteers and young trauma patients. NET response to PMA was much less pronounced in both elderly volunteers’ PMN and in trauma patients’ PMN. We conclude that mtDNA is a potent inducer of NETs that activates PMN via TLR9 without NADPH-oxidase involvement. We suggest that decreased NET formation in the elderly regardless of higher mtDNA levels in their plasma may result from decreased levels of TLR9 and/or other molecules, such as neutrophil elastase and myeloperoxidase that are involved in NET generation. Further study of the links between circulating mtDNA and NET formation may elucidate the mechanisms of trauma-related organ failure as well as the greater susceptibility to secondary infection in elderly trauma patients.
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影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1084/jem.20112322
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
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影响因子：
3.7
作者：
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通讯作者：
Itagaki K
DOI：
10.1161/atvbaha.111.242859
发表时间：
2012-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
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作者：
Fuchs TA;Brill A;Wagner DD
通讯作者：
Wagner DD
影响因子：
20.3
作者：
Sapey, Elizabeth;Greenwood, Hannah;Lord, Janet M.
通讯作者：
Lord, Janet M.