A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation.
A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation.
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DOI：
10.4049/jimmunol.1201167
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发表时间：
2012-11-01
期刊：
影响因子：
--
通讯作者：
Remold-O'Donnell E
中科院分区：
文献类型：
--
作者：
Farley K;Stolley JM;Zhao P;Cooley J;Remold-O'Donnell E
NETosis （NET generation）是由病原体和炎症介质在成熟中性粒细胞中启动的程序性死亡途径，可以是隔离微生物和防止感染扩散的保护过程，但也可以是导致炎症和严重组织损伤的病理过程。人们对其调控机制知之甚少。先前我们证明，serpinb1缺陷小鼠由于炎症和组织损伤而极易受到肺部细菌和病毒感染，这与中性粒细胞死亡增加有关。在这里，我们使用体外和体内方法来研究SerpinB1是否调节NETosis。我们发现serpinb1缺失的骨髓和肺中性粒细胞对多种介质诱导的NETosis （nadph依赖性和独立性）非常敏感，这表明serpinb1在NETosis中具有根深蒂固的调节作用。与野生型相比，经pma处理的缺乏serpinb-1的中性粒细胞的核扩张（代表染色质去浓缩）增加，SerpinB1从细胞质迁移到人类中性粒细胞的细胞核，与分叶（节段）细胞核向散裂（球形）形态的早期转化同时或之前，以及发现外源性rSerpinB1消除了NET的产生，进一步支持了这一作用。在铜绿假单胞菌肺部感染期间，体内serpinb1缺陷中性粒细胞的NETosis也增加。研究结果确定了一种以前未被认识到的涉及SerpinB1的调节机制，该机制限制了NETs的产生。
NETosis (NET generation), a programmed death pathway initiated in mature neutrophils by pathogens and inflammatory mediators, can be a protective process that sequesters microbes and prevents spread of infection, but can also be a pathological process that causes inflammation and serious tissue injury. Little is known about the regulatory mechanism. Previously we demonstrated that serpinb1-deficient mice are highly susceptible to pulmonary bacterial and viral infections due to inflammation and tissue injury associated with increased neutrophilic death. Here we used in vitro and in vivo approaches to investigate whether SerpinB1 regulates NETosis. We found that serpinb1-deficient bone marrow and lung neutrophils are hyper-susceptible to NETosis induced by multiple mediators in both NADPH-dependent and independent manner, indicating a deeply rooted regulatory role in NETosis. This role is further supported by increased nuclear expansion (representing chromatin decondensation) of PMA-treated serpinb-1-deficient neutrophils compared to wild-type, by migration of SerpinB1 from the cytoplasm to the nucleus of human neutrophils coincident with, or before, early conversion of lobulated (segmented) nuclei to delobulated (spherical) morphology, and by finding that exogenous rSerpinB1 abrogates NET production. NETosis of serpinb1-deficient neutrophils is also increased in vivo during Pseudomonas aeruginosa lung infection. The findings identify a previously unrecognized regulatory mechanism involving SerpinB1 that restricts the production of NETs.
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人骨髓中嗜中性粒细胞多形核白细胞的发展。
影响因子：
15.3
作者：
Bainton, D F;Ullyot, J L;Farquhar, M G
通讯作者：
Farquhar, M G
DOI：
10.1084/jem.20070494
发表时间：
2007-08-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Remold-O'Donnell E
DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
6.6
作者：
Olins, Ada L.;Zwerger, Monika;Olins, Donald E.
通讯作者：
Olins, Donald E.
影响因子：
5.5
作者：
Boxio, R;Bossenmeyer-Pourié, C;Nüsse, O
通讯作者：
Nüsse, O