Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis.
Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis.
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DOI：
10.1186/s12959-022-00384-0
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发表时间：
2022-04-29
影响因子：
3.1
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中科院分区：
文献类型：
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Thrombotic events cannot be completely prevented by antithrombotics, implicating a therapeutic gap due to inflammation, a not yet sufficiently addressed mechanism. Neutrophil extracellular traps (NETs) are an essential interface between inflammation and thrombosis, but exactly how the NETotic process is initiated and maintained during arterial thrombosis remains incompletely understood. We found that the plasma concentrations of C5a were higher in patients with ST-elevation myocardial infarction (STEMI) than in patients with angina and higher in mice with left common carotid artery (LCCA) thrombosis induced by FeCl3 than in control mice. We observed that the thrombus area and weight were decreased and that NET formation in the thrombi was reduced in the group treated with the selective C5aR1 receptor inhibitor PMX53 compared with the NaCl group. In vitro, NETosis was observed when C5a was added to neutrophil cultures, and this effect was reversed by PMX53. In addition, our data showed that C5a increased the production of mitochondrial reactive oxygen species (ROS) and that the promotion of NET formation by C5a was mitochondrial ROS (Mito-ROS) dependent. Furthermore, we found that C5a induced the production of Mito-ROS by inhibiting mitochondrial STAT3 activity. By inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis. The online version contains supplementary material available at 10.1186/s12959-022-00384-0.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
4.4
作者：
Fattahi, Fatemeh;Grailer, Jamison J.;Jajou, Lawrence;Zetoune, Firas S.;Andjelkovic, Anuska V.;Ward, Peter A.
通讯作者：
Ward, Peter A.
影响因子：
15.9
作者：
Levy, DE;Lee, CK
通讯作者：
Lee, CK
影响因子：
6.7
作者：
Distelmaier, Klaus;Adlbrecht, Christopher;Kubicek, Markus
通讯作者：
Kubicek, Markus
影响因子：
--
作者：
Cui, Cedric S.;Kumar, Vinod;Woodru, Trent M.
通讯作者：
Woodru, Trent M.