NETs Lead to Sympathetic Hyperactivity After Traumatic Brain Injury Through the LL37-Hippo/MST1 Pathway.
NETs Lead to Sympathetic Hyperactivity After Traumatic Brain Injury Through the LL37-Hippo/MST1 Pathway.
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NET 通过 LL37-Hippo/MST1 通路导致脑外伤后交感神经过度活跃
DOI：
10.3389/fnins.2021.621477
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发表时间：
2021
影响因子：
4.3
通讯作者：
Hou L
中科院分区：
文献类型：
--
作者：
Zhu K;Zhu Y;Hou X;Chen W;Qu X;Zhang Y;Li Z;Wang C;Chen J;Lv L;Wang J;Zhang D;Hou L
背景资料：阵发性交感神经功能亢进（PSH）是脑外伤（TBI）病死率高的重要原因之一。本研究旨在探讨中性粒细胞胞外陷阱（NETs）在创伤性脑损伤后交感神经过度兴奋发病机制中的作用，为临床治疗提供依据。研究方法：采用大鼠弥漫性轴索损伤（DAI）模型，采用酶联免疫吸附试验（ELISA）检测血浆中反映交感神经系统变化的代谢产物和正代谢产物水平。用免疫荧光和流式细胞术检测室旁核（PVN）和循环血液中的NET。建立中性粒细胞-小胶质细胞共培养体系，进一步探讨NETs对PSH的影响及其机制。结果：TBI后9 h，metane 4和normetane 4水平开始升高，72 h达高峰。伤后24和72 h，室旁核内NETs含量持续升高。PVN NETs浓度与血中儿茶酚胺浓度呈正相关。外周血细胞流式细胞仪检测结果显示，损伤组外周血NETs水平高于对照组。免疫荧光结果证实了TBI后PVN中存在NET。免疫沉淀阳性结果提示LL 37与P2 × 7之间存在相关效应。肽基精氨酸脱亚胺酶4（PAD 4）抑制剂可抑制MST 1、雅普和IL-1β的表达。hippo/MST 1通路抑制剂可抑制雅普和IL-1β的表达水平。结论：PVN内NETs的形成可能与TBI后交感神经功能亢进有关，这可能与小胶质细胞活化和通过hippo/MST 1途径增加IL-1β分泌有关。
Background: Paroxysmal sympathetic hyperactivity (PSH) is one of the important reasons for the high mortality and morbidity of traumatic brain injury (TBI). We aim to explore the role of the neutrophil extracellular traps (NETs) in the pathogenesis of sympathetic hyperexcitability after TBI and the underlying mechanisms, providing evidence for clinical treatment. Methods: Enzyme-linked immunosorbent assay was used to assess the plasma metanephrine and normetanephrine levels which represented the variation of the sympathetic system after TBI with rat diffuse axonal injury (DAI) model. NETs in the paraventricular nucleus (PVN) and circulating blood were examined using immunofluorescence and flow cytometry. Neutrophils-microglia co-culture system was established to further explore the effect of NETs on PSH and its mechanisms. Results: After TBI, metanephrine and normetanephrine levels began to increase at 9 h and peaked at 72 h. After the injury, the level of NETs kept increasing at 24 and 72 h in the PVN. A positive correlation was found between the concentration of the PVN NETs and blood catecholamine. Flow cytometry of peripheral blood cells revealed that NETs level in the injury group was higher than that in the control group. Immunofluorescence results confirmed the presence of NETs in the PVN after TBI. The positive result of immunoprecipitation suggested a correlation effect between LL37 and P2 × 7. Peptidyl arginine deiminase-4 (PAD4) inhibitor could inhibit the expression levels of MST1, YAP, and IL-1β. The hippo/MST1 pathway inhibitor could inhibit the expression levels of YAP and IL-1β. Conclusion: NETs formation in the PVN might be associated with sympathetic hyperactivity after TBI, which might relate to the activation of microglia cells and increased secretion of IL-1β via the hippo/MST1 pathway.
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DOI：
10.1126/science.aao4227
发表时间：
2018-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Albrengues J;Shields MA;Ng D;Park CG;Ambrico A;Poindexter ME;Upadhyay P;Uyeminami DL;Pommier A;Küttner V;Bružas E;Maiorino L;Bautista C;Carmona EM;Gimotty PA;Fearon DT;Chang K;Lyons SK;Pinkerton KE;Trotman LC;Goldberg MS;Yeh JT;Egeblad M
通讯作者：
Egeblad M
影响因子：
4.2
作者：
Lv, Li-Quan;Hou, Li-Jun;Lu, Yi-Cheng
通讯作者：
Lu, Yi-Cheng
影响因子：
4.7
作者：
Baguley, Ian J.
通讯作者：
Baguley, Ian J.
靶向 IL-1 Betato 抑制 Dahl 盐敏感高血压大鼠下丘脑室旁核的交感神经兴奋
影响因子：
3.2
作者：
Qi, Jie;Zhao, Xiu-Fang;Kang, Yu-Ming
通讯作者：
Kang, Yu-Ming
影响因子：
--
作者：
Bueno González AM;Corcobado Marquez MC;Portilla Botelho M;Ambrós Checa A
通讯作者：
Ambrós Checa A