Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis.
Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis.
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DOI：
10.1186/s12974-017-0801-1
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发表时间：
2017-02-07
影响因子：
9.3
通讯作者：
Friedland JS
中科院分区：
文献类型：
--
作者：
Ong CW;Pabisiak PJ;Brilha S;Singh P;Roncaroli F;Elkington PT;Friedland JS
即使接受治疗，中枢神经系统结核病(CNS-TB)也可能是致命的。中性粒细胞是结核病免疫病理的关键介质，中枢神经系统结核患者脑脊液中与中性粒细胞计数相关的基质金属蛋白酶-9(MMP9)升高与神经功能障碍和死亡密切相关。中性粒细胞驱动结核相关中枢神经系统基质破坏的机制尚不清楚。对组织学证实为CNS-TB的人脑活检组织进行中性粒细胞、中性粒细胞弹性蛋白酶和基质金属蛋白酶-9染色。Luminex和实时荧光定量聚合酶链式反应(Real-Time-PCR)分析中性粒细胞分泌及基因表达。用共聚焦显微镜和定量荧光分析评价IV型胶原的降解。用免疫印迹和化学抑制剂研究细胞内信号转导途径。在中枢神经系统结核的肉芽肿中，有中性粒细胞表达，结核分枝杆菌可上调中性粒细胞来源的基质金属蛋白酶-9的分泌。同时，结核分枝杆菌的直接刺激和单核细胞依赖网络的激活对中性粒细胞分泌基质金属蛋白酶-9有相加的作用。中和中性粒细胞基质金属蛋白酶-9可以抑制血脑屏障的关键成分--IV型胶原的破坏。单核细胞-中性粒细胞网络促进结核细胞分泌基质金属蛋白酶-9受MAP-激酶、Akt-PI3激酶通路和转录因子NF-kB的调节。肿瘤坏死因子α中和可抑制基质金属蛋白酶-9分泌至基线水平，而地塞米松不能。多条信号通路调节中性粒细胞来源的基质金属蛋白酶-9的分泌，这种分泌在中枢神经系统结核中增加。与目前用于CNS-TB的类固醇相比，这些途径可能是宿主导向治疗的更好靶点。
Central nervous system tuberculosis (CNS-TB) may be fatal even with treatment. Neutrophils are the key mediators of TB immunopathology, and raised CSF matrix metalloproteinase-9 (MMP-9) which correlates to neutrophil count in CNS-TB is associated with neurological deficit and death. The mechanisms by which neutrophils drive TB-associated CNS matrix destruction are not clearly defined. Human brain biopsies with histologically proven CNS-TB were stained for neutrophils, neutrophil elastase, and MMP-9. Neutrophil MMP-9 secretion and gene expression were analyzed using Luminex and real-time PCR. Type IV collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. Intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors. MMP-9-expressing neutrophils were present in tuberculous granulomas in CNS-TB and neutrophil-derived MMP-9 secretion was upregulated by Mycobacterium tuberculosis (M.tb). Concurrent direct stimulation by M.tb and activation via monocyte-dependent networks had an additive effect on neutrophil MMP-9 secretion. Destruction of type IV collagen, a key component of the blood-brain barrier, was inhibited by neutralizing neutrophil MMP-9. Monocyte-neutrophil networks driving MMP-9 secretion in TB were regulated by MAP-kinase and Akt-PI3 kinase pathways and the transcription factor NF-kB. TNFα neutralization suppressed MMP-9 secretion to baseline while dexamethasone did not. Multiple signaling paths regulate neutrophil-derived MMP-9 secretion, which is increased in CNS-TB. These paths may be better targets for host-directed therapies than steroids currently used in CNS-TB.