Memantine Displays Antimicrobial Activity by Enhancing Escherichia coli Pathogen-Induced Formation of Neutrophil Extracellular Traps
Memantine Displays Antimicrobial Activity by Enhancing Escherichia coli Pathogen-Induced Formation of Neutrophil Extracellular Traps
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美金刚通过增强大肠杆菌病原体诱导的中性粒细胞胞外陷阱的形成而显示出抗菌活性
DOI：
10.3389/fcimb.2020.00047
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发表时间：
2020-02
影响因子：
5.7
通讯作者：
Liqun Liu
中科院分区：
文献类型：
--
作者：
Liang Peng;Li Li;Xiaolong He;Jingyi Yu;Zhijie Zeng;Weijun Yang;Bao Zhang;Tiesong Zhang;Hong Cao;Shenghe Huang;Liqun Liu
由于多种抗生素耐药细菌的持续增加，细菌感染仍然是全球死亡的主要原因之一。仅关注细菌作为药物靶点是传统抗生素治疗固有的主要局限性。近年来，针对宿主的免疫疗法已成为调节宿主防御系统以及先天免疫和适应性免疫相互作用的一种创新方法。我们的前期研究表明，α7 nAChR拮抗剂美金刚（memantine，MEM）能有效阻断小鼠多药耐药大肠杆菌引起的菌血症和脑膜炎。然而，控制MEM抗菌作用的潜在机制仍然未知。在这项研究中，我们证明了MEM能够显着抑制E。大肠杆菌感染。大肠杆菌在体外和体内诱导NET的形成和释放。MEM能以依赖于α7 nAChR的方式促进多形核中性粒细胞（PMN）的捕获和杀菌活性，因为α7 nAChR的敲低显著降低了PMN中细菌的存活能力，而MEM不再影响PMN中细菌的存活。我们的研究结果还表明，当抗菌蛋白S100A9的表达被抑制时，病原体在PMN中的存活率显着增加。MEM以浓度依赖性方式逆转该效应。MEM刺激PMNs中MPO、S100A9和DNA的产生，并加速解聚的染色质纤维释放到细胞外空间中，表明NET的形成。综上所述，我们的数据表明，MEM通过促进由E.杆菌
Bacterial infection remains one of the leading causes of death worldwide due to the continuous rise of multiple antibiotic-resistant bacteria. Focusing solely on bacteria as the drug targets is a major limitation inherent in the conventional antibiotic therapy. Recently, host-directed therapies have become such an innovative approach to modulate the host defense system and the interplay of innate and adaptive immunity. Our previous studies showed that memantine (MEM), an α7 nAChR antagonist, could efficiently block multi-drug resistant Escherichia coli-caused bacteremia and meningitis in a mouse model. However, the underlying mechanisms that govern the antibacterial effects of MEM are still unknown. In this study, we demonstrated that MEM is able to significantly suppress E. coli infection by enhancing E. coli-induced formation and release of NETs in vitro and in vivo. MEM could promote the trapping and bactericidal activities of the polymorphonuclear neutrophils (PMNs) in a manner dependent on α7 nAChR, since knockdown of this receptor noticeably reduces the survival ability of bacteria in PMNs while MEM no longer affects the survival of bacteria in PMNs. Our results also showed that when the expression of S100A9, an antiseptic protein, is inhibited, pathogen survival rates in PMNs increase significantly. MEM reverses this effect in a concentration-dependent manner. MEM stimulates the production of MPO, S100A9, and DNA in PMNs and accelerates the release of depolymerized chromatin fibers into the extracellular space, suggesting the formation of NETs. Taken together, our data suggest that MEM effectively blocks bacterial infection through the promotion of the antibacterial function of NETs induced by E. coli.
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DOI：
10.1038/nri2566
发表时间：
2009-06
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Tracey KJ
通讯作者：
Tracey KJ
影响因子：
6.7
作者：
Achouiti A;Vogl T;Urban CF;Röhm M;Hommes TJ;van Zoelen MA;Florquin S;Roth J;van 't Veer C;de Vos AF;van der Poll T
通讯作者：
van der Poll T
影响因子：
4.8
作者：
De Filippo, Katia;Neill, Daniel R.;Hogg, Nancy
通讯作者：
Hogg, Nancy
DOI：
10.1016/j.ijantimicag.2015.08.002
发表时间：
2015-11
影响因子：
10.8
作者：
Shifu Wang;Xiaolong He;Jing-yi Yu;M. Neely;Lehai Zhang;L. Peng;Xiaolu Shi;Xinpeng Li;Sulan Wang;H. Cao;Z. Gai;Sheng-He Huang
通讯作者：
Shifu Wang;Xiaolong He;Jing-yi Yu;M. Neely;Lehai Zhang;L. Peng;Xiaolu Shi;Xinpeng Li;Sulan Wang;H. Cao;Z. Gai;Sheng-He Huang
影响因子：
7.5
作者：
Y. Yoshioka;T. Mizutani;S. Mizuta;A. Miyamoto;S. Murata;Toshiaki Ano;H. Ichise;D. Morita;Hiroyuki Yamada;Y. Hoshino;T. Tsuruyama;M. Sugita
通讯作者：
Y. Yoshioka;T. Mizutani;S. Mizuta;A. Miyamoto;S. Murata;Toshiaki Ano;H. Ichise;D. Morita;Hiroyuki Yamada;Y. Hoshino;T. Tsuruyama;M. Sugita