Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.
Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.
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DOI：
10.1371/journal.ppat.1004917
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发表时间：
2015-05
期刊：
影响因子：
6.7
通讯作者：
Friedland JS
中科院分区：
文献类型：
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作者：
Ong CW;Elkington PT;Brilha S;Ugarte-Gil C;Tome-Esteban MT;Tezera LB;Pabisiak PJ;Moores RC;Sathyamoorthy T;Patel V;Gilman RH;Porter JC;Friedland JS
肺空洞是结核病的标志，其特征是高分枝杆菌载量，并使分枝杆菌的传播永久化。结核基质破坏导致空化的机制尚未明确。中性粒细胞正在成为结核免疫病理学的关键介质，它们的流入与不良结局相关。我们使用细胞模型、108例患者队列和单独的患者肺活检研究了结核相关基质破坏中涉及的嗜中性粒细胞依赖性机制。中性粒细胞衍生的NF-κ B依赖性基质金属蛋白酶-8（MMP-8）分泌在TB中上调，并在体外和TB患者的呼吸道样本中引起基质破坏。结核感染引起的胶原破坏被多西环素（一种获得许可的MMP抑制剂）消除。中性粒细胞胞外陷阱（NET）含有MMP-8，并且在来自TB患者的样品中增加。中性粒细胞排列在人肺结核空洞的周围，痰MMP-8浓度反映了结核病的放射学和临床疾病的严重程度。AMPK是一种重要的细胞因子调节因子，它能促进中性粒细胞MMP-8的分泌，而AMPK缺乏患者的中性粒细胞分泌的MMP-8浓度较低。表达AMPK的中性粒细胞存在于人TB肺活检中，在细胞核中检测到磷酸化AMPK。这些数据表明，嗜中性粒细胞衍生的MMP-8在TB的免疫病理学中具有关键作用，并且是这种感染性疾病中宿主定向治疗的潜在靶标。中性粒细胞浸润是结核病中免疫诱导病理学的特征，但中性粒细胞引起组织破坏的机制尚未完全了解。在这项研究中，我们表明，中性粒细胞分泌的胶原酶MMP-8的直接感染结核分枝杆菌和通过细胞网络。MMP-8在来自TB患者的呼吸道样品中上调，驱动与中性粒细胞活化相关的基质破坏，并反映疾病的严重程度。在人类组织学标本中，嗜中性粒细胞存在于TB腔壁附近。代谢途径AMP活化蛋白激酶（AMPK）调节中性粒细胞MMP-8分泌，AMPK缺陷患者的人类中性粒细胞研究数据支持这一点。针对嗜中性粒细胞MMP-8的宿主导向治疗可减少TB中先天免疫介导的组织损伤。
Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease. Neutrophil infiltration is characteristic of immune-induced pathology in tuberculosis but mechanisms whereby neutrophils cause tissue destruction are not fully understood. In this study, we show that neutrophils secrete the collagenase MMP-8 in response to direct infection with Mycobacterium tuberculosis and via cellular networks. MMP-8 is up-regulated in respiratory samples from TB patients, driving matrix destruction associated with neutrophil activation and reflects disease severity. Neutrophils are present adjacent to the wall of TB cavities in human histology specimens. The metabolic pathway AMP-activated protein kinase (AMPK) regulates neutrophil MMP-8 secretion with data supported by studies in human neutrophils from AMPK-deficient patients. Host-directed therapy against neutrophil MMP-8 may reduce innate-immune mediated tissue damage in TB.
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DOI：
10.4049/jimmunol.1102975
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Guo L;Stripay JL;Zhang X;Collage RD;Hulver M;Carchman EH;Howell GM;Zuckerbraun BS;Lee JS;Rosengart MR
通讯作者：
Rosengart MR
DOI：
10.1038/nri2888
发表时间：
2011-02
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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DOI：
10.1074/jbc.m111.244772
发表时间：
2011-07-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Graham SA;Antonopoulos A;Hitchen PG;Haslam SM;Dell A;Drickamer K;Taylor ME
通讯作者：
Taylor ME
影响因子：
4.8
作者：
Chan, Olivia;Burke, J. Daniel;Fish, Eleanor N.
通讯作者：
Fish, Eleanor N.
影响因子：
64.8
作者：
通讯作者：
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