Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis.
Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis.
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DOI：
10.1371/journal.ppat.1002987
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
van der Poll T
中科院分区：
文献类型：
--
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
克雷伯氏菌(Klebsiella)肺炎是肺炎引起的败血症的常见原因。髓系相关蛋白8(MRP8，S100A8)和MRP14(S100A9)是中性粒细胞中含量最丰富的胞浆蛋白。它们可以形成MRP8/14异二聚体，在细胞应激刺激下释放。据报道，MRP8/14具有抗菌活性，但在急性暴发型脓毒症模型中，已发现MRP8/14导致器官损害和死亡。在这里，我们使用一个已建立的模型确定了MRP8/14在起源于肺部的肺炎克雷伯菌败血症中的作用，该模型的特征是细菌逐渐生长并随后传播。感染后肺组织和血浆中MRP8/14水平逐渐升高。Mrp14基因缺陷(mrp14−/−)小鼠不能形成mrp8/14异二聚体，表现为细菌传播增强，并伴有器官损伤增加和存活率下降。MRP14−/−巨噬细胞吞噬克雷伯菌的能力降低。此外，重组的MRP8/14异源二聚体，而不是单独的MRP8或MRP14，通过螯合二价阳离子来抑制克雷伯氏菌的体外生长。野生型中性粒细胞胞外陷阱(NETs)可抑制克雷伯氏菌的生长，而不是由MRP14型中性粒细胞制备的NETs；相应地，抗−/−抗体或添加锌可强烈削弱人NETs杀灭克雷伯氏菌的能力。这些结果表明，MRP8/14在肺炎克雷伯菌的保护性天然免疫中起关键作用。中性粒细胞是一种吞噬细胞，以吞噬和杀死微生物病原体的能力而闻名。越来越清楚的是，中性粒细胞还通过释放中性粒细胞胞外陷阱(Net)来杀伤或抑制细胞外生长，Net是一种用中性粒细胞衍生蛋白装饰的染色质纤维。MRP8/14已被确定为本研究中的主要抗菌蛋白之一。先前的研究表明，内源性释放的MRP8/14也被宿主感知为危险信号，并能够加强有害的全身炎症反应综合征。事实上，在暴发性全身炎症的背景下，例如内毒素或大肠杆菌注射，MRP8/14导致器官损伤和死亡。然而，脓毒症的临床情况是，最初在原发部位感染，然后细菌扩散到其他器官。在目前肺炎引发的脓毒症环境中，使用常见的人类呼吸道和败血症病原体肺炎克雷伯菌MRP8/14显然在抗菌防御方面发挥了有益的作用。我们在这里提供了一个可能的机制，表明MRP8/14在吞噬作用中发挥作用，它的存在在小鼠和人类网络中都是抑制细菌生长的关键。
Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14−/−) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14−/− macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14−/− neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia. Neutrophils are phagocytes that are well known for their capacity to engulf and kill microbial pathogens. It has become increasingly clear that neutrophils also kill or inhibit growth extracellularly by releasing neutrophil extracellular traps (NETs), chromatin fibers decorated with neutrophil derived proteins. MRP8/14 has been identified as one of the major antimicrobial proteins herein. Previous investigations have shown that endogenously released MRP8/14 is also sensed by the host as a danger signal and able to potentiate the harmful systemic inflammatory response syndrome. Indeed, in the setting of fulminant systemic inflammation, such as induced by endotoxin or Escherichia coli administration, MRP8/14 contributed to organ injury and mortality. The clinical scenario of sepsis however, involves an initial infection at the primary site followed by bacterial spreading to other organs. In the present setting of pneumonia-derived sepsis using the common human respiratory and sepsis pathogen Klebsiella pneumoniae MRP8/14 clearly served a beneficial role in antimicrobial defense. We here provide a likely mechanism by showing that MRP8/14 plays a role in phagocytosis and that its presence is critical in both murine and human NETs to inhibit bacterial growth.
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DOI：
10.1084/jem.110.1.27
发表时间：
1959-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
BENACERRAF B;SEBESTYEN MM;SCHLOSSMAN S
通讯作者：
SCHLOSSMAN S
影响因子：
2.8
作者：
Lammers, Adriana J.;de Porto, Alexander P.;van der Poll, Tom
通讯作者：
van der Poll, Tom
影响因子：
9.6
作者：
Kollef, MH;Kollef, KE
通讯作者：
Kollef, KE
影响因子：
8.8
作者：
Kumar, Arland;Roberts, Daniel;Cheang, Mary
通讯作者：
Cheang, Mary
影响因子：
30.3
作者：
Kehl-Fie TE;Chitayat S;Hood MI;Damo S;Restrepo N;Garcia C;Munro KA;Chazin WJ;Skaar EP
通讯作者：
Skaar EP