Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A.
Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A.
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DOI：
10.1371/journal.pone.0097088
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hahn S
中科院分区：
文献类型：
--
作者：
Gupta AK;Giaglis S;Hasler P;Hahn S
最近，中性粒细胞胞外陷阱（NETs）的过量或异常产生与许多人类疾病的潜在病因有关，包括先兆子痫、系统性红斑狼疮、类风湿关节炎、自身抗体诱导的小血管炎、凝血病（如深静脉血栓形成或肺部并发症）。这些结果表明，需要开发有效的药物治疗策略来对抗这些和其他炎症性疾病的明显NETosis。由于钙通量与活性氧和组蛋白瓜氨酸化的产生有关，这是NETotic过程中的两个关键事件，我们详细分析了细胞外和细胞内钙池的作用以及药物对NETotic过程的调节。白细胞介素-8 （IL-8）作为NETosis的生理刺激。我们的数据表明，NETosis的有效诱导需要动员细胞外和细胞内钙池。由于环孢素A在中性粒细胞中调节钙调磷酸酶途径，我们研究了它对NETosis的影响。我们的数据表明，IL-8诱导的NETosis被钙调神经磷酸酶途径的拮抗剂ascomycin和环孢素A减少，但在利用mTOR途径的雷帕霉素治疗后没有减少。G蛋白偶联受体磷脂酶C通路的作用似乎对IL-8诱导NETs至关重要，因为使用百日咳毒素（G蛋白抑制剂，磷脂酶C抑制剂U73122）或staurosporine（蛋白激酶C抑制剂）治疗可以减少NETosis。关于钙调磷酸酶拮抗剂，ascomycin和环孢素a的数据，打开了从治疗上抑制或调节NETosis的可能性。他们也为这种免疫抑制药物使移植患者易受机会性真菌感染的机制提供了新的见解。
Excessive or aberrant generation of neutrophil extracellular traps (NETs) has recently become implicated in the underlying aetiology of a number of human pathologies including preeclampsia, systemic lupus erythromatosus, rheumatoid arthritis, auto-antibody induced small vessel vasculitis, coagulopathies such as deep vein thrombosis or pulmonary complications. These results imply that effective pharmacological therapeutic strategies will need to be developed to counter overt NETosis in these and other inflammatory disorders. As calcium flux is implicated in the generation of reactive oxygen species and histone citrullination, two key events in NETosis, we analysed the roles of both extra- and intracellular calcium pools and their modulation by pharmacological agents in the NETotic process in detail. Interleukin-8 (IL-8) was used as a physiological stimulus of NETosis. Our data demonstrate that efficient induction of NETosis requires mobilisation of both extracellular and intracellular calcium pools. Since modulation of the calcineurin pathway by cyclosporine A has been described in neutrophils, we investigated its influence on NETosis. Our data indicate that IL-8 induced NETosis is reduced by ascomycin and cyclosporine A, antagonists of the calcineurin pathway, but not following treatment with rapamycin, which utilizes the mTOR pathway. The action of the G protein coupled receptor phospholipase C pathway appears to be essential for the induction of NETs by IL-8, as NETosis was diminished by treatment with either pertussis toxin, a G-protein inhibitor, the phospholipase C inhibitor, U73122, or staurosporine, an inhibitor of protein kinase C. The data regarding the calcineurin antagonists, ascomycin and cyclosporine A, open the possibility to therapeutically supress or modulate NETosis. They also provide new insight into the mechanism whereby such immune suppressive drugs render transplant patients susceptible to opportunistic fungal infections.
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DOI：
10.1161/atvbaha.111.242859
发表时间：
2012-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Fuchs TA;Brill A;Wagner DD
通讯作者：
Wagner DD
影响因子：
2.7
作者：
Gupta, AK;Hasler, P;Hahn, S
通讯作者：
Hahn, S
影响因子：
4
作者：
Bréchard, S;Bueb, JL;Tschirhart, EJ
通讯作者：
Tschirhart, EJ
影响因子：
14.8
作者：
Hakkim, Abdul;Fuchs, Tobias A.;Waldmann, Herbert
通讯作者：
Waldmann, Herbert
DOI：
10.1083/jcb.200606027
发表时间：
2007-01-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fuchs TA;Abed U;Goosmann C;Hurwitz R;Schulze I;Wahn V;Weinrauch Y;Brinkmann V;Zychlinsky A
通讯作者：
Zychlinsky A