Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline.
Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline.
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DOI：
10.1002/ijc.28908
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发表时间：
2014-12-01
影响因子：
6.4
通讯作者：
Kettenmann H
中科院分区：
文献类型：
--
作者：
Hu F;Ku MC;Markovic D;Dzaye O;Lehnardt S;Synowitz M;Wolf SA;Kettenmann H
恶性胶质瘤的侵袭性是胶质瘤治疗的主要障碍之一，也是影响患者生存率的主要原因。胶质瘤细胞浸润到脑实质中，从而逃避手术切除。胶质瘤相关的小胶质细胞/巨噬细胞通过增加细胞外基质降解蛋白酶如基质金属蛋白酶2、基质金属蛋白酶9和膜型1基质金属蛋白酶的表达和活化来支持胶质瘤浸润到脑实质中。在这项工作中，我们证明，基质金属蛋白酶9主要表达的胶质瘤相关的小胶质细胞/巨噬细胞在小鼠和人类胶质瘤组织，但不是由胶质瘤细胞。胶质瘤细胞培养上清诱导小胶质细胞表达基质金属蛋白酶9。使用不同的Toll样受体缺陷的小鼠，我们确定Toll样受体2/6作为神经胶质瘤诱导的小胶质细胞基质金属蛋白酶9上调的信号通路。同样在实验小鼠胶质瘤模型中，Toll样受体2缺陷减弱了小胶质细胞基质金属蛋白酶9的上调。此外，胶质瘤上清液触发小胶质细胞中Toll样受体2表达的上调。两者，基质金属蛋白酶9和Toll样受体2的上调被抗生素米诺环素和p38丝裂原活化蛋白激酶拮抗剂在体外减弱。二甲胺四环素也延长了胶质瘤荷瘤小鼠的生存率，当给予饮用水。因此，胶质瘤细胞改变胶质瘤相关的小胶质细胞/巨噬细胞的表型，在一个复杂的方式使用Toll样受体2作为一个重要的信号转导途径和米诺环素进一步证明是一个潜在的候选人胶质瘤辅助治疗。
The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix-metalloprotease 2, matrix-metalloprotease 9 and membrane-type 1 matrix metalloprotease. In this work we demonstrate that, matrix-metalloprotease 9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of matrix-metalloprotease 9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signalling pathway for the glioma induced upregulation of microglial matrix-metalloprotease 9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial matrix-metalloprotease 9. Moreover, glioma supernatant triggered an upregulation of Toll-like receptor 2 expression in microglia. Both, the upregulation of matrix-metalloprotease 9 and Toll-like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signalling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy.