Macrophage elastase kills bacteria within murine macrophages.
Macrophage elastase kills bacteria within murine macrophages.
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DOI：
10.1038/nature08181
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发表时间：
2009-07-30
期刊：
影响因子：
64.8
通讯作者：
Shapiro, Steven D.
中科院分区：
文献类型：
--
作者：
Houghton, A. McGarry;Hartzell, William O.;Robbins, Clinton S.;Xavier Gomis-Rueth, F.;Shapiro, Steven D.
巨噬细胞被恰当地定位为许多器官中抵御入侵病原体的主要防线，包括肺和腹膜。它们吞噬和清除微生物的能力已经得到了很好的证明。巨噬细胞拥有几种可以杀死细菌的物质，包括活性氧、一氧化氮和抗菌蛋白。我们认为巨噬细胞衍生的蛋白水解酶可能与巨噬细胞的抗菌特性有关。巨噬细胞弹性蛋白酶(又称基质金属蛋白酶12或MMP12)是一种主要在成熟组织巨噬细胞中表达的酶，与包括肺气肿在内的多种疾病过程有关。MMP12的生理功能尚未被描述。在这里，我们显示，当在富含巨噬细胞的入口(如腹膜和肺)同时感染革兰氏阴性和革兰氏阳性细菌时，MMP12−/−小鼠表现出细菌清除受损和死亡率增加。巨噬细胞吞噬病原体后，MMP12在细胞内的储存被动员到巨噬细胞溶酶体上。一旦进入吞噬素体，MMP12就会附着在细菌细胞壁上，破坏细胞膜，导致细菌死亡。MMP12的抗微生物特性不存在于其催化结构域中，而是存在于其羧基末端结构域中。这个结构域在暴露的蛋白质的β环上包含一个独特的四个氨基酸序列，这是观察到的抗菌活性所必需的。据我们所知，本研究首次报道了基质金属肽酶的直接抗菌活性，并描述了一种在序列和结构上具有独特性的新的抗菌肽。
Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that macrophage-derived proteinases may contribute to the antimicrobial properties of macrophages. Macrophage elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12−/− mice exhibit impaired bacterial clearance and increased mortality when challenged with both Gram-negative and Gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed β loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.
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DOI：
10.1111/paa.1999.111.5.390
发表时间：
1999-09-01
期刊：
PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS
影响因子：
--
作者：
Ganz, T
通讯作者：
Ganz, T
影响因子：
6
作者：
Limb, GA;Matter, K;Khaw, PT
通讯作者：
Khaw, PT
影响因子：
4.4
作者：
del Cerro-Vadillo, E;Madrazo-Toca, F;Alvarez-Dominguez, C
通讯作者：
Alvarez-Dominguez, C
影响因子：
3.1
作者：
HIEMSTRA, PS;EISENHAUER, PB;LEHRER, RI
通讯作者：
LEHRER, RI
影响因子：
64.5
作者：
Vu, TH;Shipley, JM;Werb, Z
通讯作者：
Werb, Z